Histone demethylase KDM5B is a key regulator of genome stability

Abstract

Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domaincontaining histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA-damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1-and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity.chromatin modification | histone methylation | genome maintenance T he ability of cells to maintain genome integrity is vital for cellular homeostasis. Defects in the maintenance of genome stability underlie a number of developmental disorders and human diseases including cancer (1-3). Compared with other types of DNA lesions, DNA double-strand breaks (DSBs) are particularly dangerous to cells because failure to repair these kinds of damage in an appropriate manner can cause cell death, and aberrant repair can lead to gross chromosomal abnormalities that may eventually lead to tumorigenesis (1, 2, 4).Upon detection of DSBs, cells activate local and global DNA damage response (DDR) events that promote cell-cycle checkpoint activation and DNA repair signaling (5, 6). For example, in response to DSBs, phosphorylation of the histone variant H2AX (γH2AX) by DDR protein kinases such as ataxia telangiectasia mutated (ATM) (7) creates an extensive modified chromatin environment that allows spatiotemporal redistribution and accumulation of checkpoint and repair factors, including DNAdamage check point-1 (MDC1) and breast cancer susceptibility gene 1 (BRCA1), into repair centers, forming microscopically visible nuclear aggregates known as foci (4, 8). The two extensively studied DSB repair pathways are homologous recombination (HR) and nonhomologous end-joining (NHEJ) (2, 9). In NHEJ, the DSB ends are blocked from 5′ end resection and held in a close proximity by DSB end-binding protein complex, the Ku70-Ku80 heterodimer (10). NHEJ promotes direct ligation of the DSB end...

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

“…Meanwhile, the resection defect in USP7-depleted cells was overcome by overexpression of PHF8, but not that of BLM (Supplemental stably integrating with an EJ5-I-SceI cassette ( Figure 7F and ref. 49) revealed that depletion of PHF8 was associated with a reduced percentage of GFP-positive cells ( Figure 7G, left panel). Together, these experiments indicate that PHF8 is required for efficient NHEJ and HR repair of DSBs in mammalian cells.…”

Histone modifications in DNA damage response

“…At first, LSD1 (lysine-specific demethylase 1), as well as its Caenorhabditis elegans ortholog Spr-5, is enriched on double-strand break sites and responsible for H3K4me1/2 demethylation, resulting in increased recruitment of repair factors (Mosammaparast et al, 2013;Nottke et al, 2011). In addition, KDM5A and KDM5B, the H3K4me2/3 demethylases, are recruited to damaged DNA to induce loss of H3K4me2/3, and required for efficient DNA repair (Li et al, 2014;Seiler et al, 2011). However, the role of H3K4 methylation in DNA damage response is disputable, because it has been reported that the yeast Set1p methyltransferase as well as its substrate H3K4me3 become detectable on a newly created double-strand break in budding yeast cells, and this enrichment of Set1p and H3K4me3 are important for DNA repair by NHEJ (Faucher and Wellinger, 2010).…”

Age-Associated DNA Methylation Changes in Naive CD4 + T Cells Suggest an Evolving Autoimmune Epigenotype in Aging T Cells

“…CpG sites hypermethylated or hypomethylated with age were depleted in PHF8 and KDM5B transcription factor binding sites (PHF8 p = 5.54 × 10 -84 and 1.47 × 10 -25 , KDM5B p = 1.06 × 10 -52 and 1.03 × 10 -16 for hypermethylated and hypomethylated age-associated CpG sites, respectively). Both transcription factors are members of the Jumonji family of proteins that play a role in chromatin remodeling and histone demethylation [51,52] ( Figure 4 & Supplementary Table 3). …”