Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links

Abstract

Cells deficient in the Werner syndrome protein (WRN) or BRCA1 are hypersensitive to DNA interstrand cross-links (ICLs), whose repair requires nucleotide excision repair (NER) and homologous recombination (HR). However, the roles of WRN and BRCA1 in the repair of DNA ICLs are not understood and the molecular mechanisms of ICL repair at the processing stage have not yet been established. This study demonstrates that WRN helicase activity, but not exonuclease activity, is required to process DNA ICLs in cells and that WRN cooperates with BRCA1 in the cellular response to DNA ICLs. BRCA1 interacts directly with WRN and stimulates WRN helicase and exonuclease activities in vitro. The interaction between WRN and BRCA1 increases in cells treated with DNA cross-linking agents. WRN binding to BRCA1 was mapped to BRCA1 452–1079 amino acids. The BRCA1/BARD1 complex also associates with WRN in vivo and stimulates WRN helicase activity on forked and Holliday junction substrates. These findings suggest that WRN and BRCA1 act in a coordinated manner to facilitate repair of DNA ICLs.

3-Methyladenine DNA glycosylase is important for cellular resistance to psoralen interstrand cross-links

“…Monoubiquitination of FANCD2 promotes BRCA2 loading into chromatin complexes, that are required for normal homologydirected DNA repair [38,39]. In addition, it was suggested that the pre-mRNA spliceosome complex Pso4 together with the Werner helicase are required for ICL processing, in coordination with BRAC1 [40,41]. The complexity, the different possible repair pathways, and the variety of proteins involved in ICL repair, raise several questions: how is ICL repair initiated?…”

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

“…The BLM RecQ helicase functions at telomeres to regulate the D‐loop formation following strand invasion and may also be involved in resolving recombination events in mortal and telomerase‐positive cells as well as in ALT‐positive human cells (Cheng et al, 2006; Acharya et al, 2014). We did not find any difference in the levels of BLM‐positive foci between the E14 and 408 cells (Fig.…”

The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

“…Cheng et al identified 29 cases of invasive breast cancer among survivors with WT and 4 cases occurred before the age of 40 [35]. Apart from treatment procedure of irradiation genetic factors may also affect tumor incidence of breast cancer in survivors of WT such as familial mutation in the BRCA1 [36] or overexpression of IGF2 gene [37].…”