Abstract
Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.
Highlights
Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability
The sequence of plant homeodomain (PHD) is highly conserved in TRIM24, TRIM33, and tripartite motif-containing 66 (TRIM66) (Supplementary Fig. 1a)
We found that the PHD domain of TRIM66 recognized unmodified H3R2K4
Summary
Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability. The aberrant deletion of Trim[66] results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). ESCs possess a more vigorous self-renewal and metabolism process compared with somatic cells, and are exposed to a higher risk of DNA damage. They exhibit a lower mutation rate[18,19,20], suggesting the presence of a more efficient DNA repair mechanism in ESCs. Reportedly, ESCs fail to activate the G1-S and intra-S checkpoints in response to DNA lesions. The key molecules and mechanisms involved in the efficient DNA damage repair (DDR) of ESCs remains to be fully elucidated
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