Chromodomain helicase DNA‐binding protein 2 affects the repair of X‐ray and UV‐Induced DNA damage

Abstract

Eukaryotic cells have evolved a variety of parallel and redundant DNA damage response pathways that function in a coordinated fashion to prevent the fixation of DNA damage as mutations. Despite the wealth of knowledge on DNA damage signaling on downstream cellular events, the mechanisms of DNA damage recognition, DNA repair as well as DNA damage signaling in the context of chromatin is poorly understood. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene. The Chd2 mutant mice are highly susceptible to spontaneous lymphoid tumor formation. In this study, we present evidence that the Chd2 mutant cells are defective in their ability to repair DNA damage induced by ionizing and ultraviolet radiation. Consistent with the role of Chd2 in regulating DNA damage responses, the Chd2 mutant cells are also sensitive to DNA damaging agents in clonogenic assays. In summary, our data suggest that the Chd2 protein is involved in regulating the DNA damage responses at the chromatin level.

ChIP-Enrich: gene set enrichment testing for ChIP-seq data

“…The most highly enriched gene sets for WHIP using the ‘≤1 kb from TSS’ definition included DNA repair ( P = 1.1 × 10 −17 ), chromatin organization ( P = 3.6 × 10 −15 ) and cell cycle regulation suggesting transcriptional roles of WHIP related to its direct function in DNA repair. Other DBPs with relatively small percentages of peaks near a TSS also showed stronger ‘≤1 kb from TSS’ enrichment results; these have known transcriptional functions and/or involvement in DNA repair (ZNF143, CHD2) (43,44), chromatin structure (EBF1) (45) or centromere formation (SMC3) (46), which may explain the lack of biological enrichment from more distal peaks (Supplementary Figure S9).…”

Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

“…There are roles for Ssh2, caldesmon, clatherins, SLC35a2, poly(A) polymerase and Chd2 in everything from actin regulation, endocytosis, galactose transport, pre-mRNA poly adenylation to chromatin structure, DNA damage responses and genomic instability [42]–[50]. Altogether, the changes in mRNA levels for these six genes suggest possible defects in cellular processes as well as potential compensatory strategies that may have been induced each different clone by the irradiation of each different parent cell.…”

The Chromodomain Helicase DNA-Binding Chromatin Remodelers: Family Traits that Protect from and Promote Cancer

“…In a follow up study, the authors found that Chd2-deficient cells are senstitive to DNA damaging agents and do not efficiently repair DNA damage induced by ultravioloet or ionizing radiation, leading them to conclude that Chd2 (like other Chd proteins, discussed below) facilitates DNA repair and maintains genomic stability. (Rajagopalan et al 2012). Yet reports using a different Chd2 compromised mouse model concluded that heterozygotes succumb to non-neoplastic lesions in a number of organs, but are not susceptible to frank cancer (Marfella et al 2006).…”