CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress.

While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.

CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle.

The protection of telomere ends by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3' single-stranded telomere end can assemble into a lasso-like t-loop configuration1,2, which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks2. Mechanisms must also exist to transiently disassemble t-loops to allow accurate telomere replication and to permit telomerase access to the 3' end to solve the end-replication problem. However, the regulation and physiological importance of t-loops in the protection of telomere ends remains unknown. Here we identify a CDK phosphorylation site in the shelterin subunit at Ser365 of TRF2, whose dephosphorylation in S phase by the PP6R3 phosphatase provides a narrow window during which the RTEL1 helicase can transiently access and unwind t-loops to facilitate telomere replication. Re-phosphorylation of TRF2 at Ser365 outside of S phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate activation of ATM, but also counteracts replication conflicts at DNA secondary structures that arise within telomeres and across the genome. Hence, a phospho-switch in TRF2 coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.

The association between serum magnesium and chronic kidney disease in Chinese adults: a cross-sectional study.

BACKGROUND: Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults. METHODS: A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multivariable logistic regression model was used to examine the relationship of serum Mg concentrations with the risk of CKD. RESULTS: Included were 8,277 individuals, with an overall CKD prevalence of 11.8% (n = 977). Compared with the first quartile of serum Mg, the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for participants in the second, third, and fourth quartiles of serum Mg were 0.74 (0.58, 0.93), 0.87 (0.69, 1.11) and 1.29 (1.03, 1.61), respectively. Similar results were observed in our several sensitivity analyses. Restricted cubic spline analysis demonstrated a nonlinear (similar "J"-shaped) association between serum Mg concentrations and the risk of CKD (Pnonlinearity <0.001), with a threshold at around a serum Mg value of 2.2 mg/dL. CONCLUSIONS: Our results suggested a similar "J"-shaped association between serum Mg concentration and the risk of CKD among Chinese adults. Further large prospective studies are needed to verify these findings.

Association of urinary and seminal plasma vanadium concentrations with semen quality: A repeated-measures study of 1135 healthy men.

Although animal studies have shown the reproductive toxicity of vanadium, less is known about its effects on semen quality in humans. Among 1135 healthy men who were screened as potential semen donors, we investigated the relationships of semen quality with urinary and seminal plasma vanadium levels via inductively coupled plasma-mass spectrometry (ICP-MS). Spearman rank correlation tests and linear regression models were used to assess the correlations between average urinary and within-individual pooled seminal plasma vanadium concentrations (n = 1135). We utilized linear mixed-effects models to evaluate the associations of urinary and seminal plasma vanadium levels (n = 1135) with repeated sperm quality parameters (n = 5576). Seminal plasma vanadium concentrations were not significantly correlated with urinary vanadium concentrations (r = 0.03). After adjusting for possible confounders, we observed inverse relationships of within-individual pooled seminal plasma vanadium levels with total count, semen volume, and sperm concentration (all P values for trend < 0.05). Specifically, subjects in the highest (vs. lowest) tertile of seminal plasma vanadium concentrations had - 11.3% (-16.4%, -5.9%), - 11.1% (-19.1%, -2.4%), and - 20.9% (-29.0%, -11.8%) lower sperm volume, concentration, and total count, respectively; moreover, urinary vanadium levels appeared to be negatively associated with sperm motility. These relationships showed monotonically decreasing dose-response patterns in the restricted cubic spline analyses. Our results demonstrated a poor correlation between urinary and seminal plasma levels of vanadium, and elevated vanadium concentrations in urine and seminal plasma may be adversely related to male semen quality.

Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1.

We identified Mte1 (Mph1-associated telomere maintenance protein 1) as a multifunctional regulator of Saccharomyces cerevisiae Mph1, a member of the FANCM family of DNA motor proteins important for DNA replication fork repair and crossover suppression during homologous recombination. We show that Mte1 interacts with Mph1 and DNA species that resemble a DNA replication fork and the D loop formed during recombination. Biochemically, Mte1 stimulates Mph1-mediated DNA replication fork regression and branch migration in a model substrate. Consistent with this activity, genetic analysis reveals that Mte1 functions with Mph1 and the associated MHF complex in replication fork repair. Surprisingly, Mte1 antagonizes the D-loop-dissociative activity of Mph1-MHF and exerts a procrossover role in mitotic recombination. We further show that the influence of Mte1 on Mph1 activities requires its binding to Mph1 and DNA. Thus, Mte1 differentially regulates Mph1 activities to achieve distinct outcomes in recombination and replication fork repair.

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.

P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

A high-resolution mass spectrometric approach to a qualitative and quantitative comparative metabolism of the humantenine-type alkaloid rankinidine.

RATIONALE: Rankinidine belongs to the humantenine-type alkaloids isolated from Gelsemium. Currently, the mechanism behind the toxicity differences of rankinidine has not been explained. In this study, our purpose was to elucidate the major in vitro metabolic pathways of rankinidine and to compare the formation of metabolites of rankinidine in human (HLMs), rat (RLMs), goat (GLMs) and pig (PLMs) liver microsomes. METHODS: This is the first study to compare the in vitro metabolism of rankinidine with high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF). The MS/MS data and LC/MS peak area acquired in positive ion mode were used to analyze metabolite structures and compare metabolism. RESULTS: We identified 11 metabolites (M1-M11) in total and found five main metabolic pathways, consisting of demethylation (M1), reduction (M2), oxidation at different positions (M3-M5), oxidation and reduction (M6-M10) and demethylation and oxidation (M11). The metabolism of rankinidine has qualitative and quantitative species-specific differences in vitro. In PLMs and GLMs, the main metabolic pathway of rankinidine was oxidation. Notably, among the four species, the oxidation ability of rankinidine was highest in pigs and goats, and the demethylation and reduction abilities of rankinidine were highest in humans and rats. CONCLUSIONS: The interspecific metabolic differences of rankinidine in HLMs, PLMs, GLMs and RLMs were compared and studied for the first time using LC/QTOF. These findings will certainly support future studies of rankinidine metabolism in vivo and will contribute to elucidating the cause of species-specific differences behind Gelsemium toxicity.

MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.

FANCM is a Fanconi anemia nuclear core complex protein required for the functional integrity of the FANC-BRCA pathway of DNA damage response and repair. Here we report the isolation and characterization of two histone-fold-containing FANCM-associated proteins, MHF1 and MHF2. We show that suppression of MHF1 expression results in (1) destabilization of FANCM and MHF2, (2) impairment of DNA damage-induced monoubiquitination and foci formation of FANCD2, (3) defective chromatin localization of FA nuclear core complex proteins, (4) elevated MMC-induced chromosome aberrations, and (5) sensitivity to MMC and camptothecin. We also provide biochemical evidence that MHF1 and MHF2 assemble into a heterodimer that binds DNA and enhances the DNA branch migration activity of FANCM. These findings reveal critical roles of the MHF1-MHF2 dimer in DNA damage repair and genome maintenance through FANCM.

A new flavonostilbene glycoside and four new stilbene derivatives from the roots of Polygonum multiflorum.

One new flavonostilbene glycoside, polygonflavanol C (1), two new dimeric stilbene glycosides, multiflorumiside M and multiflorumiside N (2-3), one new diphenyl ethanol glycoside, (R)-2,3,5,4'-tetrahydroxy-diphenylethanol 2-O-ß-D-glucopyranoside (4), and one new deoxybenzoin glycoside, 2,4,3',5'-tetrahydroxy-6-methyl-deoxybenzoin 2-O-ß-D-glucopyranoside (5), together with six known ones (6-11), were isolated from the roots of Polygonum multiflorum. Their structures were elucidated by the comprehensive spectroscopic analyses. In addition, compounds 1 and 7 showed significantly in vitro anti-inflammatory activity.

Effect of endoscopic therapy and drug therapy on prognosis and rebleeding in patients with esophagogastric variceal bleeding.

Esophagogastric variceal bleeding (EVB) is one of the common digestive system emergencies with poor prognosis and high rate of rebleeding after treatment. To explore the effects of endoscopic therapy and drug therapy on the prognosis and rebleeding of patients with EVB, and then select better treatment methods to effectively improve the prognosis. From January 2013 to December 2022, 965 patients with EVB who were hospitalized in gastroenterology Department of the 940 Hospital of Joint Logistic Support Forces of PLA were retrospectively analyzed. Patients were divided into endoscopic treatment group (ET, n = 586) and drug treatment group (DT, n = 379). Propensity score matching (PSM) analysis was performed in both groups, and the general information, efficacy and length of hospital stay were recorded. The patients were followed up for 3 months after bleeding control to determine whether rebleeding occurred. There were 286 cases in each group after PSM. Compared with DT group, ET had higher treatment success rate (P < 0.001), lower rebleeding rate (P < 0.001), lower mortality rate within 3 months, and no significant difference in total hospital stay (P > 0.05). Compared with drug therapy, endoscopic treatment of EVB has short-term efficacy advantages, and can effectively reduce the incidence of rebleeding and mortality within 3 months.

A variant of the breast cancer type 2 susceptibility protein (BRC) repeat is essential for the RECQL5 helicase to interact with RAD51 recombinase for genome stabilization.

The BRC repeat is a structural motif in the tumor suppressor BRCA2 (breast cancer type 2 susceptibility protein), which promotes homologous recombination (HR) by regulating RAD51 recombinase activity. To date, the BRC repeat has not been observed in other proteins, so that its role in HR is inferred only in the context of BRCA2. Here, we identified a BRC repeat variant, named BRCv, in the RECQL5 helicase, which possesses anti-recombinase activity in vitro and suppresses HR and promotes cellular resistance to camptothecin-induced replication stress in vivo. RECQL5-BRCv interacted with RAD51 through two conserved motifs similar to those in the BRCA2-BRC repeat. Mutations of either motif compromised functions of RECQL5, including association with RAD51, inhibition of RAD51-mediated D-loop formation, suppression of sister chromatid exchange, and resistance to camptothecin-induced replication stress. Potential BRCvs were also found in other HR regulatory proteins, including Srs2 and Sgs1, which possess anti-recombinase activities similar to that of RECQL5. A point mutation in the predicted Srs2-BRCv disrupted the ability of the protein to bind RAD51 and to inhibit D-loop formation. Thus, BRC is a common RAD51 interaction module that can be utilized by different proteins to either promote HR, as in the case of BRCA2, or to suppress HR, as in RECQL5.

Rad5-dependent DNA repair functions of the Saccharomyces cerevisiae FANCM protein homolog Mph1.

Interstrand cross-links (ICLs) covalently link complementary DNA strands, block DNA replication, and transcription and must be removed to allow cell survival. Several pathways, including the Fanconi anemia (FA) pathway, can faithfully repair ICLs and maintain genomic integrity; however, the precise mechanisms of most ICL repair processes remain enigmatic. In this study we genetically characterized a conserved yeast ICL repair pathway composed of the yeast homologs (Mph1, Chl1, Mhf1, Mhf2) of four FA proteins (FANCM, FANCJ, MHF1, MHF2). This pathway is epistatic with Rad5-mediated DNA damage bypass and distinct from the ICL repair pathways mediated by Rad18 and Pso2. In addition, consistent with the FANCM role in stabilizing ICL-stalled replication forks, we present evidence that Mph1 prevents ICL-stalled replication forks from collapsing into double-strand breaks. This unique repair function of Mph1 is specific for ICL damage and does not extend to other types of damage. These studies reveal the functional conservation of the FA pathway and validate the yeast model for future studies to further elucidate the mechanism of the FA pathway.

Risk factors of infection among close contacts of COVID-19: A systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was first detected in December 2019, and declared as a pandemic by the World Health Organization (WHO) on March 11, 2020. The current management of COVID-19 is based generally on supportive therapy and treatment to prevent respiratory failure. METHODS: PubMed, Web of Science, Embase, CNKI, and other databases were searched by computer, and relevant literature published from December 2019 to November 2022 on the influencing factors of infection in close contacts with novel coronavirus pneumonia was collected. Meta-analysis was carried out after literature screening, quality assessment, and data extraction. RESULTS: A total of 425 articles were retrieved and 11 were included. Meta-analysis showed that there were 6 risk factors, and the combined OR value and 95% CI of each influencing factor were 5.23 (3.20, 8.57) for family members, 1.63 (0.56, 4.77) for regular contact, 2.14 (0.62, 7.32) for the elderly, 0.58 (0.001569.89) for cohabitation, 1.97 (1.02, 3.82) for women and 0.75 (0.01, 54.07) for others. The Deeks' funnel diagram indicates that there is no potential publication bias among the included studies. CONCLUSION: Family members and gender differences are the risk factors of infection among close contacts, and it cannot be proved that there are differences in infection among frequent contact, advanced age, and living together.

[Expressions of HSP 70 and NF-kappaB in the peripheral blood lymphocyte of chronic gastritis patients of different syndrome patterns].

OBJECTIVE: To study the expressions of heat shock protein 70 (HSP 70) and nuclear factor-kappa B (NF-kappaB) in the peripheral blood lymphocyte of chronic gastritis (CG) patients of Pi-Wei hygropyrexia syndrome (PWHS) and Pi-qi deficiency syndrome (PQDS), and to explore their correlation with Helicobacter pylori (Hp) infection. METHODS: Recruited were totally 86 CG patients who visited at the clinics of gastroenterology, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, including 67 patients of PWHS (30 of predominant-dampness, 30 of equal dampness and heat, and 30 of predominant-heat) and 19 patients of PQDS. Another 12 volunteers from healthy employees and students of Guangzhou University of Traditional Chinese Medicine were recruited as the control group. Their peripheral blood was collected. The Hp infection was detected using ASSURE Hp rapid test. The expressions of HSP 70 and NF-kappaB in the peripheral blood lymphocyte were detected using flow cytometry. RESULTS: The Hp infection rate was 37. 31% in the GS patients of PWHS and 36. 84% in the GS patients of PQDS (P>0.05). Compared with the control group, the expression of HSP 70 decreased in the PWHS predominant-heat group, and the expression of NF-kappaB increased in the PWHS predominant-heat group and the PQDS group (P<0.05). The expression of NF-kappaB were higher in the positive Hp infection patients of PWHS and PQDS than in the control group (P<0.05). The expression of HSP 70 was higher in the positive Hp infection patients of PQDS than in the negative Hp infection patients of PQDS (P<0.05). Besides, the coefficient correlation was -0. 023 between HSP 70 and Hp infection, and 0. 027 between NF-KB and Hp infection (P>0.05). CONCLUSIONS: The increased expression of NF-KB in the peripheral blood lymphocyte of CG patients of PWHS and PQDS might reflect the pathogenic roles of "inner evil" in Chinese medicine theories. The increased expression of HSP 70 in CG patients of PQDS and decreased expression of HSP 70 in CG patients of PWHS might reflect "vital qi fighting against evils" and "exuberance evils and feeble vital qi" in the body. Hp infection might not be the only factor resulting in the occurrence of PWHS or PQDS.

[Study of Th1/Th2 balance in peripheral blood of chronic gastritis patients with Pi-Wei damp-heat syndrome].

OBJECTIVE: To study the correlation between the Th1/Th2 balance in the peripheral blood and Pi-Wei damp-heat syndrome (PDS) in chronic gastritis (CG). METHODS: Fifty-one patients with CG of PDS were recruited, including 22 cases with predominant damp (PDS-D), 9 case with predominant heat (PDS-H), and 20 case with simultaneous onset of damp and Heat (PDS-DH). Besides, 10 healthy volunteers were recruited as the healthy control group. H. pylori (HP) infection was detected by fast urea enzyme, and the expressions of Th1 type cytokines interferon-gamma (IFN-gamma), interleukin-12 (IL-12), and Th2 type cytokines interleukin-4 (IL-4), interleukin-10 (IL-10) in serum were detected by luminex technology. RESULTS: The HP infection rate was 41.18% (21/51) in the PDS patients, obviously higher than that in the healthy control group (10.00%,1/10), showing statistical difference (P<0.05). The HP infection rate was 45.45% (10/22) in PDS-D, 22.22% (2/9) in PDS-H, and 45.00% (9/20) in PDS-DH. The HP infection rate in PDS-D and PDS-DH was significantly higher than that of the healthy control group, showing statistical difference (P<0.05). There was no statistically significant difference in the expressions of peripheral blood IFN-gamma, IL-12, IL-4, and IL-10 between the PDS patient group and the healthy control group (P>0.05). But the expressions of IFN-gamma and IL-12 showed an increasing trend in the PDS patient group, while the expression of IL-4 showed a decreasing trend. The expressions of IFN-gamma, IL-12, IL-4, and the ratios of IFN-gamma/IL-4 and IL-12/IL-4 were also higher in PDS-DH group than in the PDS-D group and the PDS-H group, but with no statistical significance (P>0.05). CONCLUSION: The occurrence of Pi-Wei damp-heat CG was possibly correlated with the imbalance of Th1/Th2. Damp and heat pathogen might be important pathogenic factors leading to Th1 type cytokine immunoreaction.

Suppressive Effects of Gelsemine on Anxiety-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice.

Gelsemine is an active principle and a major alkaloid found in Gelsemium genus of plants belonging to the Loganiaceae family. The aim of the present study was to explore whether gelsemine exerts anxiolytic effects on a mouse model of chronic-unpredictable-mild-stress (CUMS)-induced anxiety-like behaviors. NOD-like receptor protein 3 (NLRP3) inflammasome, downregulated cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were also evaluated as potential mechanisms. First, gelsemine reversed a CUMS-induced decrease in body-weight gain in mice. Next, gelsemine alleviated CUMS-induced anxiety-like behaviors, as evidenced by the increased distance traveled in the central zone of the open-field test, both the increased percentage of time spent and distance traveled in the light compartment, the increased number of transitions between compartments in the light/dark-transition test, and the increased percentage of entries and time spent in the open arm of the elevated plus-maze. In addition, gelsemine decreased the levels of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6, in the hypothalamus and hippocampus of CUMS mice. Interestingly, further investigations revealed that gelsemine inhibited the CUMS-induced activation of NLRP3-inflammasome pathways and downregulated CREB and BDNF overexpression in the hypothalamus. In summary, gelsemine alleviated anxiety-like behaviors in the CUMS-induced mouse model. Gelsemine exerted its anxiolytic effects by modulating the NLRP3 and CREB/BDNF pathways.

Ca2+-PKCα-ERK1/2 signaling pathway is involved in the suppressive effect of propofol on proliferation of neural stem cells from the neonatal rat hippocampus.

Neonatal exposure to propofol induces persistent behavioral abnormalities in adulthood. In addition to triggering the apoptosis of neurons in the developing brain, anesthetics may contribute to the development of cognitive deficits by interfering neurogenesis. Given the importance of neural stem cell (NSC) proliferation in neurogenesis, the effect of propofol on NSC proliferation and the mechanisms underlying this effect were investigated. Hippocampal NSC proliferation from neonatal rats was examined using 5-bromo-2'-deoxyuridine incorporation assays in vitro. The [Ca2+]i was analyzed using flow cytometry. The activations of protein kinase C (PKC)-α and extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot. Our results showed that propofol significantly inhibited NSC proliferation in vitro. [Ca2+]i and activations of PKCα and ERK1/2 in NSCs were markedly suppressed by propofol (5, 10, 20, 40 and 80 µM). Ca2+ channel blocker verapamil, PKCα inhibitor chelerythrine and ERK1/2 kinase inhibitor PD98059 exerted their maximal effects on NSC function at concentrations of 20, 10 and 20 µM, respectively. Propofol (20 µM) could not produce further additional suppression effects when used in combination with verapamil (20 µM), chelerythrine (10 µM) or PD98059 (20 µM). In addition, phorbol-12-myristate-13-acetate (PMA, a activator of PKC) markedly attenuated the suppressive effects of propofol on ERK1/2 phosphorylation and NSC proliferation. The inhibition effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation induced by propofol were significantly improved by BayK8644 (a calcium channel agonist). These results indicate that propofol can inhibits hippocampal NSC proliferation by suppressing the Ca2+-PKCα-ERK1/2 signaling pathway.

A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1.

Mitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3ß, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3ß phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.