Impact of eliminating visual input on sitting posture and head position in a patient with spatial neglect following cerebral hemorrhage: a case report.

Background: Spatial neglect is a neurocognitive syndrome. Affected individuals pay little or insufficient attention to the space contralateral to the injured cerebral hemisphere, often resulting in or exacerbating disability following an acquired brain injury. Eliminating visual input may increase attention toward the contralesional side of space, and improve symptoms of spatial neglect; however this has never been examined in a clinical setting. Objective: In this case report, we observed an individual demonstrate immediate and spontaneous postural changes once visual input was eliminated. Methods: The patient, a 53-year-old female, was admitted to a rehabilitation hospital after hemorrhagic stroke affecting her right basal ganglia and surrounding regions in the frontal lobe. She exhibited left-sided spasticity, severe right gaze preference, and stark rightward postural deviation. Neck passive range of motion was normal. Visual field integrity was inconclusive due to poor communication and impaired cognitive function. Contraversive pushing was ruled out. Results:Once visual input was eliminated by applying a blindfold, the patient turned to the left spontaneously, had more buttock contact on the left, and placed more weight toward the left side in a sitting posture. However, she returned to rightward deviation three minutes after blindfold removal. In addition, the patient's rehabilitation team reported that she was able to participate in more therapy activities with binocular occlusion than with eyes open. Conclusion: Binocular occlusion appeared to demonstrate an immediate, albeit transient, improvement in postural symmetry. The results warrant further research and exploration in clinical applicability.

What Determines the Quality of Rehabilitation Clinical Practice Guidelines?: An Overview Study.

OBJECTIVE: The aim of the study was to determine what factors determine the quality of rehabilitation clinical practice guidelines. DESIGN: Six databases were searched for articles that had applied the Appraisal of Guidelines for Research & Evaluation II quality assessment tool to rehabilitation clinical practice guidelines. The 573 deduplicated abstracts were independently screened by two authors, resulting in 81 articles, the full texts of which were independently screened by two authors for Appraisal of Guidelines for Research & Evaluation II application to rehabilitation clinical practice guidelines, resulting in a final selection of 40 reviews appraising 504 clinical practice guidelines. Data were extracted from these by one author and checked by a second. Data on each clinical practice guideline included the six Appraisal of Guidelines for Research & Evaluation II domain scores, as well as the two Appraisal of Guidelines for Research & Evaluation II global evaluations. RESULTS: All six Appraisal of Guidelines for Research & Evaluation II domain scores were statistically significant predictors of overall clinical practice guideline quality rating; D3 (rigor of development) was the strongest and D1 (scope and purpose) the weakest (overall model P < 0.001, R2 = 0.53). Five of the six domain scores were significant predictors of the clinical practice guideline use recommendation, with D3 the strongest predictor and D5 (applicability) the weakest (overall model P < 0.001, pseudo R2 = 0.53). CONCLUSIONS: Quality of rehabilitation clinical practice guidelines may be improved by addressing key domains such as rigor of development.

Quality of Rehabilitation Clinical Practice Guidelines: An Overview Study of AGREE II Appraisals.

OBJECTIVE: To evaluate the quality of rehabilitation Clinical Practice Guidelines (CPG), specifically with respect to their applicability. DATA SOURCES: The Medline, Embase, Web of Science, CINAHL, PsycINFO, and Cochrane Library databases were searched for papers published between 2017 and 2019 that applied the Appraisal of Guidelines for Research & Evaluation II (AGREE II) CPG quality assessment tool to rehabilitation CPGs. STUDY SELECTION: Deduplicated abstracts (N=449) were independently screened by 2 authors, resulting in 47 articles. Independent screening of 47 full texts by 2 authors resulted in a final selection of 40 papers appraising 544 CPGs. DATA EXTRACTION: Data were extracted by 1 author using a pretested Excel form and were checked by a second author. Key data on the review papers included: purpose, methods used for finding and appraising CPGs, and observations and conclusions on CPG quality, specifically applicability. Key data on each CPG included the 6 AGREE II domain scores or 23 item scores, as well as 2 global evaluations. DATA SYNTHESIS: The mean AGREE II domain scores for the 544 CPGs (all on a 0-100 scale) were: scope and purpose (72), stakeholder involvement (53), rigor of development (56), clarity of presentation (71), applicability (34), and editorial independence (50). Only 36% of CPGs were recommended without modification. The 40 review authors generally stated that all or most of the CPGs they appraised were poor or mediocre, especially with respect to applicability. They only infrequently pointed out what information, going beyond that specified in AGREE II, would enhance applicability. CONCLUSIONS: CPGs in principle are an ideal means to move knowledge obtained from clinical research into practice. Our review of reviews of rehabilitation CPGs shows that they commonly have deficits, especially in terms of applicability. Much work needs to be done by guideline developers to make it easier for the average rehabilitation organization and clinician to implement CPGs in daily practice.

Clinical Practice Guideline to Improve Locomotor Function Following Chronic Stroke, Incomplete Spinal Cord Injury, and Brain Injury.

BACKGROUND: Individuals with acute-onset central nervous system (CNS) injury, including stroke, motor incomplete spinal cord injury, or traumatic brain injury, often experience lasting locomotor deficits, as quantified by decreases in gait speed and distance walked over a specific duration (timed distance). The goal of the present clinical practice guideline was to delineate the relative efficacy of various interventions to improve walking speed and timed distance in ambulatory individuals greater than 6 months following these specific diagnoses. METHODS: A systematic review of the literature published between 1995 and 2016 was performed in 4 databases for randomized controlled clinical trials focused on these specific patient populations, at least 6 months postinjury and with specific outcomes of walking speed and timed distance. For all studies, specific parameters of training interventions including frequency, intensity, time, and type were detailed as possible. Recommendations were determined on the basis of the strength of the evidence and the potential harm, risks, or costs of providing a specific training paradigm, particularly when another intervention may be available and can provide greater benefit. RESULTS: Strong evidence indicates that clinicians should offer walking training at moderate to high intensities or virtual reality-based training to ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. In contrast, weak evidence suggests that strength training, circuit (ie, combined) training or cycling training at moderate to high intensities, and virtual reality-based balance training may improve walking speed and distance in these patient groups. Finally, strong evidence suggests that body weight-supported treadmill training, robotic-assisted training, or sitting/standing balance training without virtual reality should not be performed to improve walking speed or distance in ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. DISCUSSION: The collective findings suggest that large amounts of task-specific (ie, locomotor) practice may be critical for improvements in walking function, although only at higher cardiovascular intensities or with augmented feedback to increase patient's engagement. Lower-intensity walking interventions or impairment-based training strategies demonstrated equivocal or limited efficacy. LIMITATIONS: As walking speed and distance were primary outcomes, the research participants included in the studies walked without substantial physical assistance. This guideline may not apply to patients with limited ambulatory function, where provision of walking training may require substantial physical assistance. SUMMARY: The guideline suggests that task-specific walking training should be performed to improve walking speed and distance in those with acute-onset CNS injury although only at higher intensities or with augmented feedback. Future studies should clarify the potential utility of specific training parameters that lead to improved walking speed and distance in these populations in both chronic and subacute stages following injury. DISCLAIMER: These recommendations are intended as a guide for clinicians to optimize rehabilitation outcomes for persons with chronic stroke, incomplete spinal cord injury, and traumatic brain injury to improve walking speed and distance.

Understanding the Level of Concussion Knowledge in High School Sports in New Jersey.

BACKGROUND: Coaches, athletic trainers (ATCs), and parents/guardians (parents) are important contributors to the proper identification and management of concussions in student-athletes. However, there are limited studies on the identification of concussion knowledge gaps that will help inform educational efforts and improve concussion outcomes in these groups. OBJECTIVE: To identify gaps and factors influencing concussion knowledge for high school athletics. DESIGN: Survey. SETTING: Public, private, and recreational leagues in New Jersey. PARTICIPANTS: 41 coaches, 34 ATCs, and 65 parents of high school student-athletes. METHODS: A 17-item online survey examining concussion knowledge was distributed to coaches, ATCs, and parents. Analyses included ANOVA for between-group comparisons of continuous variables and Pearson's correlations for categorical data. MAIN OUTCOME MEASUREMENTS: Demographics, concussion knowledge, application of knowledge, access to educational materials, and confidence in the ability to identify concussions. RESULTS: Significant between-group differences were found for overall knowledge (F[2137] = 11.0, P < .001), factual knowledge (F[2137] = 8.7, P < .001), and application of knowledge (F[2137] = 3.5, P = .03), with parents scoring lower. Coaches, ATCs, and parents had gaps in factual knowledge of baseline testing scores and identification regarding symptom severity. More coaches (73.2%) and ATCs (97.1%) felt confident in concussion knowledge compared with parents (31.3%; P < .001). All groups thought mandatory education, new law, and guidelines were positive in promoting better care of student-athletes. CONCLUSIONS: Knowledge gaps were identified in all groups. Educational programs for these groups should consider including targeted techniques, including vignettes, to illustrate application of concussion knowledge. LEVEL OF EVIDENCE: III.

Feasibility and Preliminary Validation of an Online Version of the Ohio State University Traumatic Brain Injury Identification Method.

OBJECTIVE: To test the feasibility and validity of an online version of an established interview designed to determine a lifetime history of traumatic brain injury (TBI). DESIGN: Cross-sectional. SETTING: General community. PARTICIPANTS: A volunteer sample of individuals (N= 265) from the general population across the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Online version of the Ohio State University Traumatic Brain Injury Identification Method, Rivermead Postconcussion Symptoms Questionnaire (RPQ), Patient-Reported Outcomes Measurement Information System Cognitive Concerns Scale. RESULTS: The measure was completed by 89.4% of the sample with most participants completing the measure in <8 minutes. After controlling for age, sex, psychiatric history, drug or alcohol history, and history of developmental disability, worst TBI severity was significantly associated with scores on the RPQ, F(2,230)=4.56, P=.011, and having a TBI within the past 2 years was associated with higher scores on the cognitive factor subscale of the RPQ, F(1,75)=7.7, P=.007. CONCLUSIONS: The online administration of the Ohio State University Traumatic Brain Injury Identification Method appears to be feasible in the general population. Preliminary validity was demonstrated for the indices of worst TBI severity and time since most recent TBI.

The therapeutic value of cranioplasty in individuals with brain injury.

PRIMARY OBJECTIVE: To examine the effect of cranioplasty on recovery. RESEARCH DESIGN: Retrospective cohort study. METHOD AND PROCEDURES: Retrospective chart review conducted in 2011 and 2012 on adult inpatients with craniectomy who completed a continuous episode of inpatient rehabilitation before and after receiving their cranioplasty. Patients were matched 1:1 or age, gender, functional level at admission, injury severity and length of stay with inpatients who completed rehabilitation before cranioplasty. Main outcome measures include FIMTM (Functional Independence Measure) and FIMTM efficiency [(FIMTM discharge - FIMTMadmission)/number of days in rehabilitation]. To examine within and between group differences, analyses included paired and independent t-tests, Pearson correlations and chi-square analyses. RESULTS: Twenty-six individuals (13 from the cranioplasty group and 13 from the comparison group) were analysed. FIMTM efficiency increased following cranioplasty [0.29 to 0.61; t(12) = -2.77, p = 0.017]. The mean FIMTM efficiency for the cranioplasty group was below that of the comparison group prior to cranioplasty [0.28 ± 0.37 and 0.39 ± 0.32, p = .41], but increased following cranioplasty [0.61 ± 0.71 and 0.39 ± 0.32, p = .32]. An improvement in FIMTM efficiency following cranioplasty was more commonly seen among individuals with less severe brain injuries (75%, χ2 = 3.8, df = 1, p = 0.053). CONCLUSION: Rate of recovery increased following cranioplasty and exceeded that of the comparison group suggesting that cranioplasty may contribute to improvement.

Outcome Measures for Persons With Moderate to Severe Traumatic Brain Injury: Recommendations From the American Physical Therapy Association Academy of Neurologic Physical Therapy TBI EDGE Task Force.

BACKGROUND AND PURPOSE: The use of standardized outcome measures (OMs) is essential in assessing the effectiveness of physical therapy (PT) interventions. The purposes of this article are (1) to describe the process used by the TBI EDGE task force to assess the psychometrics and clinical utility of OMs used with individuals with moderate to severe traumatic brain injury (TBI); (2) to describe the consensus recommendations for OM use in clinical practice, research, and professional (entry-level) PT education; and (3) to make recommendations for future work. METHODS: An 8-member task force used a modified Delphi process to develop recommendations on the selection of OMs for individuals with TBI. A 4-point rating scale was used to make recommendations based on practice setting and level of ambulation. Recommendations for appropriateness for research use and inclusion in entry-level education were also provided. RESULTS: The TBI EDGE task force reviewed 88 OMs across the International Classification of Functioning, Disability, and Health (ICF) domains: 15 measured body functions/structure only, 21 measured activity only, 23 measured participation only, and 29 OMs covered more than 1 ICF domain. DISCUSSION AND CONCLUSIONS: Recommendations made by the TBI EDGE task force provide clinicians, researchers, and educators with guidance for the selection of OMs. The use of these recommendations may facilitate identification of appropriate OMs in the population with moderate to severe TBI. TBI EDGE task force recommendations can be used by clinicians, researchers, and educators when selecting OMs for their respective needs. Future efforts to update the recommendations are warranted in order to ensure that recommendations remain current and applicable.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A140).

Presence of a dedicated trauma center physiatrist improves functional outcomes following traumatic brain injury.

BACKGROUND: Maximizing long-term recovery following traumatic brain injury (TBI) is an important end point. We hypothesized that the addition of a dedicated physiatrist specializing in brain injury medicine to the trauma team would lead to improved functional outcomes. METHODS: Data from the Northern NJ TBI Model Systems were queried for all patients admitted to rehabilitation from four regional trauma centers, one with a full-time TBI physiatrist (PHYS) and three without (NO-PHYS). Patient demographics, mechanism of injury, Glasgow Coma Scale (GCS) score, length of posttraumatic amnesia, length of stay, and Functional Independence Measure (FIM) were abstracted. TBI severity was determined by GCS score and length of posttraumatic amnesia. FIM motor and cognitive scores at rehabilitation admission and discharge were the primary outcome measure. TBI medications (stimulants, sleep, and neurodepressants) administered in acute care were reviewed to evaluate prescription patterns. RESULTS: A total of 148 patients treated at four trauma centers and discharged to a single acute inpatient rehabilitation center between 2005 to 2013 were divided into two groups, PHYS with 44 patients and NO-PHYS with 104 patients. Compared with those in the NO-PHYS group, patients from the PHYS group had significant improvement in FIM motor and cognitive scores (p < 0.05). Prescription patterns differed. Patients from the PHYS group received significantly more neurostimulants (p < 0.001) and sleep medications (p = 0.02) compared with the NO-PHYS group. Analysis of covariance was conducted to examine FIM (motor and cognitive) changes from rehabilitation admission to discharge based on medications initiated in acute care. Those who received neither a neurostimulant nor a sleep medication had significantly lower FIM motor scores compared with those who received at least one of these medications (p = 0.047) and compared with those who received both types of medication (p = 0.17). No significant differences were found in FIM cognitive scores. CONCLUSION: The addition of a dedicated physiatrist providing early specialized care to patients who sustained a moderate or severe TBI was associated with improved functional outcomes upon discharge from rehabilitation. The presence of a dedicated trauma center physiatrist, trained in TBI rehabilitation, was also associated with a change in neuroprotective medication management in the acute care setting. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Spatial Neglect Hinders Success of Inpatient Rehabilitation in Individuals With Traumatic Brain Injury: A Retrospective Study.

Background Current knowledge about spatial neglect and its impact on rehabilitation mostly originates from stroke studies. Objective To examine the impact of spatial neglect on rehabilitation outcome in individuals with traumatic brain injury (TBI). Methods The retrospective study included 156 consecutive patients with TBI (73 women; median age = 69.5 years; interquartile range = 50-81 years) at an inpatient rehabilitation facility (IRF). We examined whether the presence of spatial neglect affected the Functional Independence Measure (FIM) scores, length of stay, or discharge disposition. Based on the available medical records, we also explored whether spatial neglect was associated with tactile sensation or muscle strength asymmetry in the extremities and whether specific brain injuries or lesions predicted spatial neglect. Results In all, 30.1% (47 of 156) of the sample had spatial neglect. Sex, age, severity of TBI, or time postinjury did not differ between patients with and without spatial neglect. In comparison to patients without spatial neglect, patients with the disorder stayed in IRF 5 days longer, had lower FIM scores at discharge, improved slower in both Cognitive and Motor FIM scores, and might have less likelihood of return home. In addition, left-sided neglect was associated with asymmetric strength in the lower extremities, specifically left weaker than the right. Finally, brain injury-induced mass effect predicted left-sided neglect. Conclusions Spatial neglect is common following TBI, impedes rehabilitation progress in both motor and cognitive domains, and prolongs length of stay. Future research is needed for linking specific traumatic injuries and lesioned networks to spatial neglect and related impairment.

Validity of the stroke rehabilitation assessment of movement scale in acute rehabilitation: a comparison with the functional independence measure and stroke impact scale-16.

OBJECTIVE: To demonstrate sensitivity to change of the Stroke Rehabilitation Assessment of Movement (STREAM) as well as the concurrent and predictive validity of the STREAM in an acute rehabilitation setting. DESIGN: Prospective cohort study. SETTING: Acute, in-patient rehabilitation department within a tertiary-care teaching hospital in the United States. PARTICIPANTS: Thirty adults with a newly diagnosed, first ischemic stroke. METHODS: Clinical assessments were conducted on admission and then again on discharge from the rehabilitation hospital with the STREAM (total STREAM and upper extremity, lower extremity, and mobility subscales), Functional Independence Measure (FIM), and Stroke Impact Scale-16 (SIS-16). Sensitivity to change was determined with the Wilcoxon signed rank test and by the calculation of standardized response means. Spearman correlations were used to assess concurrent validity of the total STREAM and STREAM subscales with the FIM and SIS-16 on admission and discharge. We determined predictive validity for all instruments by correlating admission scores with actual and predicted length of stay and by testing associations between admission scores and discharge destination (home vs subacute facility). MAIN OUTCOMES: Not applicable. RESULTS: For all instruments, there was statistically significant improvement from admission to discharge. The standardized response means for the total STREAM and STREAM subscales were large. Spearman correlations between the total STREAM and STREAM subscales and the FIM and SIS-16 were moderate to excellent, both on admission and discharge. Among change scores, only the SIS-16 correlated with the total STREAM. All 3 instruments were significantly associated with discharge destination; however, the associations were strongest for the total STREAM and STREAM subscales. All instruments showed moderate-to-excellent correlations with predicted and actual length of stay. CONCLUSIONS: The STREAM is sensitive to change and demonstrates good concurrent and predictive validity as compared with the FIM and SIS-16 in the acute inpatient rehabilitation population.

Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis.

The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.

Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair.

Histone lysine methylation has been linked to the recruitment of mammalian DNA repair factor 53BP1 and putative fission yeast homolog Crb2 to DNA double-strand breaks (DSBs), but how histone recognition is achieved has not been established. Here we demonstrate that this link occurs through direct binding of 53BP1 and Crb2 to histone H4. Using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, we show that, despite low amino acid sequence conservation, both 53BP1 and Crb2 contain tandem tudor domains that interact with histone H4 specifically dimethylated at Lys20 (H4-K20me2). The structure of 53BP1/H4-K20me2 complex uncovers a unique five-residue 53BP1 binding cage, remarkably conserved in the structure of Crb2, that best accommodates a dimethyllysine but excludes a trimethyllysine, thus explaining the methylation state-specific recognition of H4-K20. This study reveals an evolutionarily conserved molecular mechanism of targeting DNA repair proteins to DSBs by direct recognition of H4-K20me2.

The tandem BRCT domain of 53BP1 is not required for its repair function.

53BP1 plays an important role in cellular response to DNA damage. It is thought to be the mammalian homologue of budding yeast Rad9 and/or fission yeast Crb2. Rad9/Crb2 are bona fide checkpoint proteins whose activation requires their corresponding C-terminal tandem BRCT (BRCA1 C-terminal) motifs, which mediate their oligomerization and phosphorylation at multiple sites following DNA damage. Here we show that the function of human 53BP1 similarly depends on its oligomerization and phosphorylation at multiple sites but in a BRCT domain-independent manner. Moreover, unlike its proposed yeast counterparts, human 53BP1 only has limited checkpoint functions but rather acts as an adaptor in the repair of DNA double strand breaks. This difference in function may reflect the higher complexity of the DNA damage response network in metazoa including the evolution of other BRCT domain-containing proteins that may have functions redundant or overlapping with those of 53BP1.

53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice.

p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1-/- p53-/- lymphomas, like those in H2AX-/- p53-/- mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/- mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1-/- p53+/+ and 53BP1-/- p53-/- tumors as well as in primary 53BP1-/- splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.

Chfr is required for tumor suppression and Aurora A regulation.

Tumorigenesis is a consequence of loss of tumor suppressors and activation of oncogenes. Expression of the mitotic checkpoint protein Chfr is lost in 20-50% of primary tumors and tumor cell lines. To explore whether downregulation of Chfr contributes directly to tumorigenesis, we generated Chfr knockout mice. Chfr-deficient mice are cancer-prone, develop spontaneous tumors and have increased skin tumor incidence after treatment with dimethylbenz(a)anthracene. Chfr deficiency leads to chromosomal instability in embryonic fibroblasts and regulates the mitotic kinase Aurora A, which is frequently upregulated in a variety of tumors. Chfr physically interacts with Aurora A and ubiquitinates Aurora A both in vitro and in vivo. Collectively, our data suggest that Chfr is a tumor suppressor and ensures chromosomal stability by controlling the expression levels of key mitotic proteins such as Aurora A.

Early events in the DNA damage response.

The ability to sense DNA damage and activate response pathways that coordinate cell cycle progression and DNA repair is essential for the maintenance of genomic integrity and the viability of organisms. During the last couple of years, several proteins have been identified that participate very early in the DNA damage response. Here we review the current understanding of the mechanisms by which mammalian cells detect DNA lesions, especially double-strand breaks, and mediate the signal to downstream transducers.

Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest.

Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of gamma-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.

53BP1 is required for class switch recombination.

53BP1 participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BP1 would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BP1. Moreover, 53BP1-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for "classic" nonhomologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked.