Resolving the Conflict between Transcription and DNA Repair during DNA Damage

DNA damage occurs continuously following exposure to endogenous and exogenous damaging agents. To repair damaged DNA and preserve genomic stability, eukaryotic cells developed sophisticated and highly efficient DNA damage response (DDR). Several reports showed that DNA damage triggers rapid and transient transcription pause to restrict the production of aberrant transcripts from damaged loci and to prevent deleterious collisions between transcription and repair machineries. However, little is known about the mechanisms that ensure transcription repression following DNA damage. Here, we present 3 novel DDR players that contribute to transcriptional silencing following double-strand breaks (DSBs) induction. First, the negative transcription elongation factor (NELF) is recruited to DSB near transcriptionally active genes to inhibit RNA Polymerase II transcription elongation and facilitate DSB repair [1]. Second, chromodomain Y-like (CDYL1) protein mediates transcription repression by altering the histone code via recruiting EZH2 to damaged DNA and stimulating the local increase in the repressive methyl mark H3K27me3[2]. Third, HDACs which are recruited to DNA damage sites to remove the transcriptionally active lysine crotonylation mark [3]. In summary, our data provides molecular insights into the mechanism by which the cells ensure transient transcription silencing at DNA breakage sites.

References

1. Awwad SW, Abu-Zhayia ER, Guttmann-Raviv N, Ayoub N (2017) NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. EMBO Rep 18: 745-764
2. Abu-Zhayia ER, Awwad SW, Ben-Oz BM, Khoury-Haddad H, Ayoub N (2018) CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair. J Mol Cell Biol 10: 341-357
3. Abu-Zhayia ER*, Machour FE*, Ayoub N (2019) HDAC-dependent decrease in histone crotonylation during DNA damage. J Mol Cell Biol

* equal contribution