The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin

Abstract

Efficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes can facilitate different DNA repair pathways, during different stages of the cell cycle and in a range of chromatin environments. The contribution of remodelling factors to break repair within heterochromatin during G2 is unclear. The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We find that HELLS facilitates homologous recombination at two-ended breaks within heterochromatic regions during G2. HELLS enables end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.

Gata2a maintains cebpa and npm1a in haematopoietic stem cells to sustain lineage differentiation and genome stability

“…3G) were downregulated in mHSPCs, suggesting a decrease in proliferation (Shinya et al, 2014;Snyder et al, 2005) consistent with the cytopenic phenotype noted at 6mpf. In addition we noted a decrease in genes required for DNA repair and genome stability, such as hells (Kollárovič et al, 2020), npm1a (Grisendi et al, 2005;Koike et al, 2010) and ncl (Kawamura et al, 2019;Scott and Oeffinger, 2016) (Fig. 3G).…”

Moving Mountains—The BRCA1 Promotion of DNA Resection

“…For example, the chromatin-binding protein Lens epithelium-derived growth factor (LEDGF) binds preferentially to epigenetic methyl-lysine histone markers characteristic of active transcription and also interacts with CtIP in a damage dependent way, thereby improving resection within active genomic regions (Daugaard et al, 2012). In addition, specialist remodelers, such as the Snf2-like remodeler Helicase, lymphoid specific (HELLS), appear to enable HDR at some heterochromatic regions (Kollarovic et al, 2019) and heterochromatin-resident proteins such as HP1 and Sentrin/SUMO-Specific Protease SENP7 (SENP7) nevertheless facilitate HDR (Garvin et al, 2013; Lee et al, 2013). A recent study using CRISPR-Cas9 to quantify HDR- and NHEJ-derived gene editing events at single-target sequences subjected to distinct chromatin conformations found that NHEJ and not HDR was more sensitive to chromatin state.…”