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Structure and functional analysis of the BRCT domain of translesion synthesis DNA polymerase rev1

机译：跨病变合成DNA聚合酶rev1的BRCT结构域的结构和功能分析

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摘要

Translesion synthesis (TLS) is a pathway in which specialized, low-fidelity DNA polymerases are used to overcome replication blocks caused by DNA damage. The use of this pathway often results in somatic mutations that can drive carcinogenesis. Rev1 is a TLS polymerase found in all eukaryotes that plays a pivotal role in mediating DNA damage-induced mutagenesis. It possesses a BRCA1 C-terminal (BRCT) domain that is required for its function. The rev1-1 allele encodes a mutant form of Rev1 with a G193R substitution in this domain, which reduces the level of DNA damage-induced mutagenesis. Despite its clear importance in mutagenic TLS, the role of the BRCT domain is unknown. Here, we report the X-ray crystal structure of the yeast Rev1 BRCT domain and show that substitutions in residues constituting its phosphate-binding pocket do not affect mutagenic TLS. This suggests that the role of the Rev1 BRCT domain is not to recognize phosphate groups on protein binding partners or on DNA. We also found that residue G193 is located in a conserved turn region of the BRCT domain, and our in vivo and in vitro studies suggest that the G193R substitution may disrupt Rev1 function by destabilizing the fold of the BRCT domain.
机译：跨病变合成（TLS）是一种途径，在该途径中，使用了专门的低保真DNA聚合酶来克服由DNA损伤引起的复制障碍。使用该途径通常会导致体细胞突变，从而导致癌变。 Rev1是在所有真核生物中发现的TLS聚合酶，在介导DNA损伤诱导的诱变中起关键作用。它具有功能所需的BRCA1 C端（BRCT）域。 rev1-1等位基因编码Rev1的突变形式，在该结构域中具有G193R取代，从而降低了DNA损伤诱导的诱变水平。尽管在诱变TLS中具有明显的重要性，但BRCT域的作用尚不清楚。在这里，我们报告酵母Rev1 BRCT域的X射线晶体结构，并表明构成其磷酸盐结合袋的残基中的取代不影响诱变TLS。这表明Rev1 BRCT域的作用不是识别蛋白质结合伴侣或DNA上的磷酸基。我们还发现，残基G193位于BRCT结构域的保守转折区域，我们的体内和体外研究表明，G193R取代可能通过破坏BRCT结构域的折叠来破坏Rev1功能。

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