CDCA7 and HELLS suppress DNA: RNA hybrid‑associated DNA damage at pericentromeric repeats

DOI IR (HANDLE) PDF Web Site PubMed 5 Citations 39 References Open Access

Bibliographic Information

Other Title
  • CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats

Description

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that is caused by mutations in either DNMT3B, ZBTB24, CDCA7, HELLS, or yet unidentified gene(s). Previously, we reported that the CDCA7/HELLS chromatin remodeling complex facilitates non-homologous end-joining. Here, we show that the same complex is required for the accumulation of proteins on nascent DNA, including the DNMT1/UHRF1 maintenance DNA methylation complex as well as proteins involved in the resolution or prevention of R-loops composed of DNA:RNA hybrids and ssDNA. Consistent with the hypomethylation state of pericentromeric repeats, the transcription and formation of aberrant DNA:RNA hybrids at the repeats were increased in ICF mutant cells. Furthermore, the ectopic expression of RNASEH1 reduced the accumulation of DNA damage at a broad range of genomic regions including pericentromeric repeats in these cells. Hence, we propose that hypomethylation due to inefficient DNMT1/UHRF1 recruitment at pericentromeric repeats by defects in the CDCA7/HELLS complex could induce pericentromeric instability, which may explain a part of the molecular pathogenesis of ICF syndrome.

Journal

Citations (5)*help

See more

References(39)*help

See more

Related Projects

See more

Keywords

Details 詳細情報について

Report a problem

Back to top