Methylated-UHRF1 and PARP1 Interaction Is Critical for Homologous Recombination

Abstract

A recent study suggested that methylation of ubiquitin-like with PHD and RING finger domain 1 (UHRF1) is regulated by SET7 and lysine-specific histone demethylase 1A (LSD1) and is essential for homologous recombination (HR). The study demonstrated that SET7-mediated methylation of UHRF1 promotes polyubiquitination of proliferating cell nuclear antigen (PCNA), inducing HR. However, studies on mediators that interact with and recruit UHRF1 to damaged lesions are needed to elucidate the mechanism of UHRF1 methylationinduced HR. Here, we identified that poly [ADP-ribose] polymerase 1 (PARP1) interacts with damage-induced methylated UHRF1 specifically and mediates UHRF1 to induce HR progression. Furthermore, cooperation of UHRF1-PARP1 is essential for cell viability, suggesting the importance of the interaction of UHRF1-PARP1 for damage tolerance in response to damage. Our data revealed that PARP1 mediates the HR mechanism, which is regulated by UHRF1 methylation. The data also indicated the significant role of PARP1 as a mediator of UHRF1 methylation-correlated HR pathway. [BMB Reports 2020; 53(2): 112-117] BMB Rep. 2020; 53(2): 112-117 www.bmbreports.org UHRF1 and PARP1 promote homologous recombination Ja Young Hahm, et al. 113 http://bmbreports.org BMB Reports

The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity

“…In specific conditions, the same residue can be differentially modified to obtain diverse outcomes, e.g. methylation of K385 by SET7 confers the ability to promote DNA repair by homologous recombination during S phase ( 72 , 73 ), while methylation of the same residue by SET8 during G2 mediates UHRF1 destabilization and degradation ( 74 ). UHRF1 can perform auto-ubiquitination via the intrinsic ubiquitin E3 ligase activity of its RING domain ( 5 , 75 ).…”

“…Accumulation at stalled forks of RAD18-dependent mono-ubiquitinated PCNA was demonstrated to direct the repair towards the process of ICL resolution ( 107 ). All the aforementioned factors are very well-known interactors of UHRF1; many have been directly associated with UHRF1 in DNA damage ( 72 , 73 ), while others are still being evaluated. Among the latter, the interaction between the MYST domain of TIP60 and the SRA and RING domains of UHRF1 ( 47 ) is peculiar because UHRF1 is commonly associated to DNA methylation and heterochromatin formation, two processes that are not expected to be associated with histone acetylation, generally linked to chromatin relaxation and activation of transcription.…”

“…They demonstrated that phosphorylation of UHRF1 at S661 during S phase is essential for the subsequent methylation in vivo of UHRF1 at K385 by SET7; SET7 action is counteracted by the activity of LSD1 that removes the methyl group, tightly controlling the levels of methyl-UHRF1 during DNA damage response ( 72 ). This methylation is a determinant for the interaction with PARP1 and for the recruitment of UHRF1 on damaged sites ( 73 ) (Figure 3B , step 1–2). Inhibition of UHRF1–PARP1 interaction in presence of DNA damage resulted in cell cycle arrest in G2/M phase and increased apoptosis, denoting reduced efficiency in the repairing processes.…”

SET7-mediated TIP60 methylation is essential for DNA double-strand break repair

“…Additionally, we have identified that SET7-mediated UHRF1 methylation in response to DNA damage, polyubiquitinates PCNA, and promotes HR progression ( 13 ). We also reported that PARP1 is required for the recruitment of methylated UHRF1 to DNA damage sites and for the HR repair pathway ( 28 ). Several studies have indicated that SET7 is also involved in the regulation of PARP1 activity.…”

The PARP Way to Epigenetic Changes

“…PARylation seems to be required for the maintenance of heterochromatin throughout cell divisions by controlling UHFR1-DNMT1 interplay and by directing DNMT1 to euchromatin regions and hemi-methylated CpG dyads [ 97 ]. The interaction of UHRF1-PARP1 seems also essential for cell viability, as recent findings suggest its involvement in response to DNA damage [ 98 ].…”