Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Nucleotide excision repair (NER) counteracts the onset of cancer and aging by removing helix-distorting DNA lesions via a "cut-and-patch"-type reaction. The regulatory mechanisms that drive NER through its successive damage recognition, verification, incision, and gap restoration reaction steps remain elusive. Here, we show that the RAD5-related translocase HLTF facilitates repair through active eviction of incised damaged DNA together with associated repair proteins. Our data show a dual-incision-dependent recruitment of HLTF to the NER incision complex, which is mediated by HLTF's HIRAN domain that binds 3'-OH single-stranded DNA ends. HLTF's translocase motor subsequently promotes the dissociation of the stably damage-bound incision complex together with the incised oligonucleotide, allowing for an efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

DNA Damage-Induced Nucleosome Depletion Enhances Homology Search Independently of Local Break Movement.

To determine whether double-strand break (DSB) mobility enhances the physical search for an ectopic template during homology-directed repair (HDR), we tested the effects of factors that control chromatin dynamics, including cohesin loading and kinetochore anchoring. The former but not the latter is altered in response to DSBs. Loss of the nonhistone high-mobility group protein Nhp6 reduces histone occupancy and increases chromatin movement, decompaction, and ectopic HDR. The loss of nucleosome remodeler INO80-C did the opposite. To see whether enhanced HDR depends on DSB mobility or the global chromatin response, we tested the ubiquitin ligase mutant uls1Δ, which selectively impairs local but not global movement in response to a DSB. Strand invasion occurs in uls1Δ cells with wild-type kinetics, arguing that global histone depletion rather than DSB movement is rate limiting for HDR. Impaired break movement in uls1Δ correlates with elevated MRX and cohesin loading, despite normal resection and checkpoint activation.

The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis.

Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.

A comprehensive demographic profile of the US evicted population.

Millions of American renter households every year are threatened with eviction, an event associated with severe negative impacts on health and economic well-being. Yet we know little about the characteristics of individuals living in these households. Here, we link 38 million eviction court cases to US Census Bureau data to show that 7.6 million people, including 2.9 million children, faced the threat of eviction each year between 2007 and 2016. Overall, adult renters living with at least one child in their home were threatened with eviction at an annual rate of 10.4%, twice that of adults without children (5.0%). We demonstrate not only that the average evicted household includes one child, but that the most common age to experience eviction in America is during childhood. We also find that previous studies have underestimated racial disparities in eviction risk: Despite making up only 18.6% of all renters, Black Americans account for 51.1% of those affected by eviction filings and 43.4% of those evicted. Roughly one in five Black Americans living in a renter household is threatened with eviction annually, while one in ten is evicted. Black-White disparities persist across levels of income and vary by state. In providing the most comprehensive description to date of the population of US renters facing eviction, our study reveals a significant undercount of individuals impacted by eviction and motivates policies designed to stabilize housing for children and families.

Longer trips to court cause evictions.

Studying ∼200,000 evictions filed against ∼300,000 Philadelphians from 2005 to 2021, we focus on the role of transit to court in preventing tenants from asserting their rights. In this period, nearly 40% of tenants facing eviction were ordered to leave their residences because they did not show up to contest cases against them and received a default judgment. Controlling for a variety of potential confounds at the tenant and landlord level, we find that residents of private tenancies with longer transit travel time to the courthouse were more likely to default. A 1-h increase in estimated travel time increases the probability of default by between 3.8% and 8.6% points across different model specifications. The effect holds after adjusting for direct distance to the court, unobserved landlord characteristics, and even baseline weekend travel time. However, it is absent in public housing evictions, where timing rules are significantly laxer, and during the COVID-19 pandemic, when tenants had the opportunity to be present virtually. We estimate that had all tenants been equally able to get to the court in 10 min, there would have been 4,000 to 9,000 fewer default evictions over the sample period. We replicate this commuting effect in another dataset of over 800,000 evictions from Harris County, Texas. These results open up a new way to study the physical determinants of access to justice, illustrating that the location and accessibility of a courthouse can affect individual case outcomes. We suggest that increased use of video technology in court may reduce barriers to justice.

Estimating eviction prevalence across the United States.

SignificanceSeveral negative effects of forced displacement have been well documented, yet we lack reliable measurement of eviction risk in the national perspective. This prevents accurate estimations of the scope and geography of the problem as well as evaluations of policies to reduce housing loss. We construct a nationwide database of eviction filings in the United States. Doing so reveals that 2.7 million households, on average, are threatened with eviction each year; that the highest eviction filing rates are not concentrated solely in high-cost urban areas; and that state-level housing policies are strongly associated with county-level eviction filing risk. These data facilitate an expanded research agenda on the causes and consequences of eviction lawsuits in the United States.

Diversifying the anthracycline class of anti-cancer drugs identifies aclarubicin for superior survival of acute myeloid leukemia patients.

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Neighborhood eviction trajectories and odds of moderate and serious psychological distress during pregnancy among African American women.

African American mothers are unjustly burdened by both residential evictions and psychological distress. We quantified associations between trajectories of neighborhood evictions over time and the odds of moderate and serious psychological distress (MPD and SPD, respectively) during pregnancy among African American women. We linked publicly available data on neighborhood eviction filing and judgment rates to preconception and during-pregnancy addresses from the Life-course Influences on Fetal Environments (LIFE) Study (2009-2011; n = 808). Multinomial logistic regression-estimated odds of MPD and SPD during pregnancy that were associated with eviction filing and judgment rate trajectories incorporating preconception and during-pregnancy addresses (each categorized as low, medium, or high, with two 9-category trajectory measures). Psychological distress was measured with the Kessler Psychological Distress Scale (K6) (K6 scores 5-12 = MPD, and K6 scores ≥13 = SPD). MPD was reported in 60% of the sample and SPD in 8%. In adjusted models, higher neighborhood eviction filing and judgment rates, as compared with low/low rates, during the preconception and pregnancy periods were associated with 2- to 4-fold higher odds of both MPD and SPD during pregnancy among African American women. In future studies, researchers should identify mechanisms of these findings to inform timely community-based interventions and effective policy solutions to ensure the basic human right to housing for all. This article is part of a Special Collection on Mental Health.

An essential role for the Ino80 chromatin remodeling complex in regulation of gene expression during cellular quiescence.

Cellular quiescence is an important physiological state both in unicellular and multicellular eukaryotes. Quiescent cells are halted for proliferation and stop the cell cycle at the G0 stage. Using fission yeast as a model organism, we have previously found that several subunits of a conserved chromatin remodeling complex, Ino80C (INOsitol requiring nucleosome remodeling factor), are required for survival in quiescence. Here, we demonstrate that Ino80C has a key function in the regulation of gene expression in G0 cells. We show that null mutants for two Ino80C subunits, Iec1 and Ies2, a putative subunit Arp42, a null mutant for the histone variant H2A.Z, and a null mutant for the Inositol kinase Asp1 have very similar phenotypes in quiescence. These mutants show reduced transcription genome-wide and specifically fail to activate 149 quiescence genes, of which many are localized to the subtelomeric regions. Using spike in normalized ChIP-seq experiments, we show that there is a global reduction of H2A.Z levels in quiescent wild-type cells but not in iec1∆ cells and that a subtelomeric chromosome boundary element is strongly affected by Ino80C. Based on these observations, we propose a model in which Ino80C is evicting H2A.Z from chromatin in quiescent cells, thereby inactivating the subtelomeric boundary element, leading to a reorganization of the chromosome structure and activation of genes required to survive in quiescence.

Housing insecurity among black women surviving intimate partner violence during the COVID-19 pandemic: an intersectional qualitative approach.

BACKGROUND: Housing instability is highly prevalent among intimate partner violence (IPV) survivors, and the coupling consequences of structural racism, sexism, classism, and the COVID-19 pandemic, may create more barriers to safe and adequate housing, specifically for Black women IPV survivors. In particular, the consequences of the COVID-19 pandemic had the potential to amplify disadvantages for Black women IPV survivors, yet very little research has acknowledged it. Therefore, the current study sought to assess the experiences of housing insecurity among Black women experiencing intimate partner violence (IPV) while navigating racism, sexism, and classism during the COVID-19 pandemic. METHODS: From January to April 2021, we conducted in-depth interviews with 50 Black women experiencing IPV in the United States. Guided by intersectionality, a hybrid thematic and interpretive phenomenological analytic approach was used to identify sociostructural factors shaping housing insecurity. RESULTS: Our findings demonstrate the various ways in which the COVID-19 pandemic shaped Black women IPV survivors' ability to obtain and sustain safe housing. We derived five themes to capture factors contributing to housing experiences: challenges with separate and unequal neighborhoods; pandemic-related economic inequalities; economic abuse limitations; and strategies to maintain housing. CONCLUSIONS: Obtaining and maintaining safe housing during the COVID-19 pandemic was difficult for Black women IPV survivors who were also navigating racism, sexism, and socioeconomic position. Interventions are needed to reduce the impact of these intersecting systems of oppression and power to facilitate the resources necessary for Black women IPV survivors to identify safe housing.

Thioredoxin-dependent disulfide bond reduction is required for protamine eviction from sperm chromatin.

Cysteine oxidation in protamines leads to their oligomerization and contributes to sperm chromatin compaction. Here we identify the Drosophila thioredoxin Deadhead (DHD) as the factor responsible for the reduction of intermolecular disulfide bonds in protamines and their eviction from sperm during fertilization. Protamine chaperone TAP/p32 dissociates DNA-protamine complexes in vitro only when protamine oligomers are first converted to monomers by DHD. dhd-null embryos cannot decondense sperm chromatin and terminate development after the first pronuclear division. Therefore, the thioredoxin DHD plays a critical role in early development to facilitate the switch from protamine-based sperm chromatin structures to the somatic nucleosomal chromatin.

Historic Residential Redlining and Present-Day Social Determinants of Health, Home Evictions, and Food Insecurity within US Neighborhoods.

OBJECTIVE: Examine the association between historic residential redlining and present-day racial/ethnic composition of neighborhoods, racial/ethnic differences in social determinant of health domains, and risk of home evictions and food insecurity. RESEARCH DESIGN AND METHODS: We examined data on 12,334 (for eviction sample), and 8996 (for food insecurity sample), census tracts in 213 counties across 37 states in the USA with data on exposure to historic redlining. First, we examined relationships between Home Owners' Loan Corporation (HOLC) redlining grades (A="Best", B="Still Desirable", C="Definitely Declining", D="Hazardous") and present-day racial/ethnic composition and racial/ethnic differences in social determinant of health domains of neighborhoods. Second, we examined whether historic redlining is associated with present-day home eviction rates (measured across eviction filings rates, and eviction judgment rates for 12,334 census tracts in 2018) and food insecurity (measured across low supermarket access, low supermarket access and income, low supermarket access and low car ownership for 8996 census tracts in 2019). Multivariable regression models were adjusted for census tract population, urban/rural designation, and county level fixed effects. RESULTS: Relative to areas with a historic HOLC grading of "A (Best)", areas with a "D (Hazardous)" grading had a 2.59 (95%CI=1.99-3.19; p-value<0.01) higher rate of eviction filings, and a 1.03 (95%CI=0.80-1.27; p-value<0.01) higher rate of eviction judgments. Compared to areas with a historic HOLC grading of "A (Best)", areas rated with a "D (Hazardous)" had a 16.20 (95%CI=15.02-17.79; p-value<0.01) higher rate of food insecurity based on supermarket access and income, and a 6.15 (95%CI =5.53-6.76; p-value<0.01) higher rate of food insecurity based on supermarket access and car ownership. CONCLUSIONS: Historic residential redlining is significantly associated with present-day home evictions and food insecurity, highlighting persistent associations between structural racism and present-day social determinants of health.

Preventing eviction during pregnancy: a cost-effectiveness analysis of a theoretical safety-net program.

BACKGROUND: Eviction during pregnancy has been shown to be associated with adverse birth outcomes. A safety net program focused on covering the costs of rent during pregnancy may aid in preventing adverse complications. OBJECTIVE: This study aimed to evaluate the cost-effectiveness of a program covering the cost of rent to prevent eviction during pregnancy. STUDY DESIGN: A cost-effectiveness model using TreeAge software was designed to evaluate the cost, effectiveness, and incremental cost-effectiveness ratio associated with eviction compared to no eviction during pregnancy. The cost of eviction from a societal perspective was compared to the annual cost of housing in the no eviction group, which was estimated by the median contract rent in the United States from 2021 national census data. Birth outcomes included preterm birth, neonatal death, and major neurodevelopmental delay. Probabilities and costs were derived from the literature. The cost-effectiveness threshold was set at $100,000/QALY. We performed univariable and multivariable sensitivity analyses to assess the robustness of the results. RESULTS: In our theoretical cohort of 30,000 pregnant individuals aged 15 to 44 years facing eviction annually, the no eviction during pregnancy strategy was associated with 1427 fewer preterm births, 47 fewer neonatal deaths, and 44 fewer cases of neurodevelopmental delay compared to eviction. At the median cost of rent in the United States, the no eviction strategy was associated with increased quality-adjusted life-years and decreased costs. Therefore, the no eviction strategy was the dominant strategy. In univariate sensitivity analysis varying the cost of housing, no eviction remained the cost-effective strategy and was cost-saving when rent was below $1016 per month. CONCLUSION: The no eviction strategy is cost-effective and reduces cases of preterm birth, neonatal death, and neurodevelopmental delay. When rent is below the median of $1016 per month, no eviction is the cost-saving strategy. These findings suggest that policies supporting social programmatic implementation for rent coverage for pregnant people at risk of eviction have the potential to be highly beneficial in reducing costs and disparities in perinatal outcomes.

Is it Time to Antiquate the Term "Landlord?"

With the growth of community partnerships with housing providers to address social determinants of health, it may be time to rethink the term "landlord." The term, landlord, may be antiquated as it originated from medieval Europe in the 9th century, denotes rank, is male, and may create further divisions between tenants and landlords. In the US, many average Americans rent their property; as data from the Internal Revenue Service and the Rental Housing Finance Survey indicate nearly 10 million Americans reported rental income in 2020 and most of them own only 1-2 rental units. This commentary argues that the term "landlord" is no longer relevant, may be counterproductive to building a culture of health across stakeholder groups, and should be replaced. Some alternative terms are suggested, including "lessor" or "rental host." Accurate and neutral terms may be useful in engaging renters and property owners in addressing housing and homelessness issues in society.

Experiences with Eviction, House Foreclosure, and Homelessness Among COVID-19 Infected Adults and Their Relation to Mental Health in a Large U.S. City.

This study examined experiences with eviction, house foreclosures, and homelessness in a large U.S. city sample of adults with Coronavirus Disease-2019 (COVID-19). A total of 3595 adults with COVID-19 participated in an assessment of health and well-being after completing contact tracing activities. The sample had a 5.7% lifetime prevalence of eviction, 3.7% lifetime prevalence of house foreclosure, and 8.2% lifetime prevalence of homelessness. Relative importance analyses revealed drug use was the most important variable associated with any lifetime eviction, lifetime house foreclosure, lifetime homelessness, and being currently at-risk of eviction or recently evicted. Loneliness was also relatively strongly associated with any lifetime eviction or homelessness, while socioeconomic characteristics were the most importance variables associated with late mortgage payments in the past month. Treatment for addiction problems may be important for in the aftermath of the COVID-19 pandemic and adults with histories of housing instability may be particularly at risk.

Renter Nonpayment and Landlord Response: Evidence From COVID-19.

How renters respond to economic hardship, and how landlords respond when tenants fail to make rent, are understudied questions, owing largely to limited data. We use experiences from the COVID-19 pandemic to begin answering these questions. Drawing on both new census data and two original surveys of renters in Los Angeles County, we test nine hypotheses about the sources of renter distress and landlord reactions to it. We find that lost work and lost income are the primary drivers of missed or late payments. Most tenants who fell behind entered into repayment plans with their landlords. Eviction threats were uncommon but increased as the pandemic persisted. Landlords were more likely to threaten eviction as tenants fell further behind, and smaller landlords were more likely than larger ones to cut tenant services and threaten or initiate evictions. Our evidence suggests that government income support helped tenants pay rent and thus helped stave off eviction threats. We also find that tenants took on other forms of debt, such as credit cards, loans from family, etc., to make rent. These debt burdens generally will not be relieved by housing assistance, and so require other policy responses.

Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.

Histone H3K4me1 and H3K27ac are enhancer-specific modifications and are required for enhancers to activate transcription of target genes. However, the reciprocal effects of these histone modifications on each other and their roles in enhancers are not clear. Here to comparatively analyze the role of these modifications, we inhibited H3K4me1 and H3K27ac by deleting the SET domains of histone methyltransferases MLL3 and MLL4 and the HAT domain of histone acetyltransferase p300, respectively, in erythroid K562 cells. The loss of H3K4me1 reduced H3K27ac at the ß-globin enhancer LCR HSs, but H3K27ac reduction did not affect H3K4me1. This unequal relationship between two modifications was revealed in putative enhancers by genome-wide analysis using ChIP-seq. Histone H3 eviction at putative enhancers was weakened by the loss of H3K4me1 but not by the loss of H3K27ac. Chromatin remodeling complexes were recruited into the ß-globin LCR HSs in a H3K4me1-dependent manner. In contrast, H3K27ac was required for enhancer RNA (eRNA) transcription, and H3K4me1 was not enough for it. Forced H3K27ac-induced eRNA transcription without affecting H3K4me1 at the ß-globin LCR HSs. These results indicate that H3K4me1 and H3K27ac affect each other in different ways and play more direct roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.

Characteristics of Tenants Who Delayed Rent Payments during Eviction Moratoria in 2020.

This study examined the characteristics of US tenants who reported delaying rent payments during the eviction moratoria in 2020 in respond to the coronavirus disease 2019 (COVID-19) pandemic. A nationally representative sample of 3393 US tenants was assessed from May to June 2020 during a period that eviction moratoria were issued across the country. In the total sample, 22.9% of US tenants reported they delayed paying rent because of the eviction moratoria. Tenants who delayed paying rent were nearly 7 times as likely to be at risk of eviction, more than 3 times as likely to endorse recent suicidal ideation, and 1.6 times as likely to report recent illicit drug use compared to tenants who did not delay paying rent. These findings highlight the health and social needs of tenants in the aftermath of the COVID-19 pandemic.

A database of US state policies to mitigate COVID-19 and its economic consequences.

BACKGROUND: Since COVID-19 first appeared in the United States (US) in January 2020, US states have pursued a wide range of policies to mitigate the spread of the virus and its economic ramifications. Without unified federal guidance, states have been the front lines of the policy response. MAIN TEXT: We created the COVID-19 US State Policy (CUSP) database ( https://statepolicies.com/ ) to document the dates and components of economic relief and public health measures issued at the state level in response to the COVID-19 pandemic. Documented interventions included school and business closures, face mask mandates, directives on vaccine eligibility, eviction moratoria, and expanded unemployment insurance benefits. By providing continually updated information, CUSP was designed to inform rapid-response, policy-relevant research in the context of the COVID-19 pandemic and has been widely used to investigate the impact of state policies on population health and health equity. This paper introduces the CUSP database and highlights how it is already informing the COVID-19 pandemic response in the US. CONCLUSION: CUSP is the most comprehensive publicly available policy database of health, social, and economic policies in response to the COVID-19 pandemic in the US. CUSP documents widespread variation in state policy decisions and implementation dates across the US and serves as a freely available and valuable resource to policymakers and researchers.

Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog.

CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, a Schizosaccharomyces pombe CSB ortholog. The molecular basis of chromatin remodeling and nucleosomal epitope recognition by Rhp26 is distinct from that of canonical chromatin remodelers, such as imitation switch protein (ISWI). We reveal that the remodeling activities are bidirectionally regulated by CSB-specific motifs: the N-terminal leucine-latch motif and the C-terminal coupling motif. Rhp26 remodeling activities depend mainly on H4 tails and to a lesser extent on H3 tails, but not on H2A and H2B tails. Rhp26 promotes the disruption of histone cores and the release of free DNA. Finally, we dissected the distinct contributions of two Rhp26 C-terminal regions to chromatin remodeling and DNA damage repair.