CHFR is important for the first wave of ubiquitination at DNA damage sites

Abstract

Protein ubiquitination plays an important role in activating the DNA damage response and maintaining genomic stability. In response to DNA double-strand breaks (DSBs), a ubiquitination cascade occurs at DNA lesions. Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). At DSBs, CHFR regulates the first wave of protein ubiquitination. Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Thus, these results demonstrate that CHFR is an important E3 ligase in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation.

Base Excision Repair, a Pathway Regulated by Posttranslational Modifications

“…In a similar study, CHFR overexpressed in cells was demonstrated to be recruited to sites of laser microirradiationinduced DNA damage in a poly(ADP-ribosyl)ation-dependent manner. Poly(ADP-ribosyl)ated PARP-1 was also shown to be a target for CHFR-mediated polyubiquitylation (57). As with RNF4-mediated polyubiquitylation of SUMOylated PARP-1, this suggests a possible mechanism for displacing activated PARP-1 from DNA damage sites, therefore promoting DNA repair.…”

A Quantitative Assay Reveals Ligand Specificity of the DNA Scaffold Repair Protein XRCC1 and Efficient Disassembly of Complexes of XRCC1 and the Poly(ADP-ribose) Polymerase 1 by Poly(ADP-ribose) Glycohydrolase

“…Auto-modified PARP1 recruits a DNA repair scaffold XRCC1 to sites of DNA damage in a PAR-dependent manner (7). The PARP1-XRCC1 complex is subsequently disassembled to marshal the DNA repair activities associated with XRCC1, whereas PARP1 is polyubiquitinylated and degraded (8,9). PARylated PARP1 binds to a conserved PAR-binding motif (PBM) located in one of two BRCA1 C terminus (BRCT) domains of XRCC1 (see Fig.…”

CHFR is important for the survival of male premeiotic germ cells

“…It has been shown that CHFR is important for the first wave of protein ubiquitination at DNA damage sites. 18,19 Similar mechanisms could exist in testes as well. Interestingly, the maintenance of spermatogonial stem cells in adults is defective in both Chfr and Atm knockout male mice.…”

“…[14][15][16][17] CHFR is an E3 ubiquitin ligase and participates in DNA damage response. 18,19 It is recruited to DNA damage sites by poly(ADP-ribose) and is important for the first wave of protein ubiquitination there. 19 It functions synergistically with RNF8 to activate ATM in response to DNA damage.…”

“…18,19 It is recruited to DNA damage sites by poly(ADP-ribose) and is important for the first wave of protein ubiquitination there. 19 It functions synergistically with RNF8 to activate ATM in response to DNA damage. 18 Chfr knockout mice have been generated and are tumor-prone.…”