PhD. Graduate Seminar- Einas Abu Zhayia
09/12/2020 13:00

Identification of a novel pathway to ensure double strand break-inducedtranscriptional silencing and repair

Double-strand break (DSB) are the most cytotoxic form DNA damageand defective DSB repair leads to genomic instabilities that may augment carcinogenesis.DSBs trigger local transcriptional silencing in an ATM, DNA-PK, and PARP1-dependentmanner. During my PhD, I identified a previously unrecognized dual role ofchromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-inducedtranscriptional silencing and homology-directed repair. Mechanistically, CDYL1ensures DSB-induced transcriptional silencing by local stimulation of therepressive methyl mark H3K27me3 and down regulation of histone lysinecrotonylation. Unexpectedly, while inhibiting the reduction in lysinecrotonylation at DSB sites alleviates transcriptional silencing, the integrityof HDR of DSBs remains intact. Our results uncoupled therefore the repair andthe silencing activity of CDYL1 at DSBs. In a broader context, our dataaddressed a long-standing question in the field concerning the functionalrelationship between HDR and DSB-induced transcriptional silencing and suggestthat they may occur independently.