Genome-wide Control of Heterochromatin Replication by the Telomere Capping Protein TRF2
Genome-wide Control of Heterochromatin Replication by the Telomere Capping Protein TRF2
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DOI：
10.1016/j.molcel.2018.03.036
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发表时间：
2018-05-03
期刊：
影响因子：
16
通讯作者：
Ye, Jing
中科院分区：
文献类型：
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作者：
Mendez-Bermudez, Aaron;Lototska, Liudmyla;Ye, Jing
染色体上难以复制的区域（例如着丝粒周围、着丝粒和端粒）会阻碍复制叉的进展，最终在复制应激的情况下导致染色体脆弱、衰老和癌症。我们对控制这些区域稳定性的机制的了解基本上仅限于端粒，其中的脆弱性由庇护蛋白抵消。在这里，我们表明，shelterin 亚基 TRF2 确保复制叉通过着丝粒周围异染色质的进展，但不保证着丝粒染色质的进展。在涉及其 N 端基本结构域的过程中，TRF2 在 S 期与着丝粒周围卫星 III 序列结合，从而招募 G-四链体解旋酶 RTEL1 以促进分叉进展。我们还表明，TRF2对于位于整个基因组中的其他异染色质区域的稳定性是必需的，这为未来异染色质复制及其与衰老和癌症关系的研究铺平了道路。
Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin. In a process involving its N-terminal basic domain, TRF2 binds to pericentromeric Satellite III sequences during S phase, allowing the recruitment of the G-quadruplex-resolving helicase RTEL1 to facilitate fork progression. We also show that TRF2 is required for the stability of other heterochromatic regions localized throughout the genome, paving the way for future research on heterochromatic replication and its relationship with aging and cancer.