Laboratory of Genomic Instability and Diseases, Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India.
Mol Microbiol. 2018 Dec;110(5):707-727. doi: 10.1111/mmi.14004. Epub 2018 Oct 30.
Polη, a unique TLS DNA polymerase that promotes efficient bypass of UV-induced CPDs and cisplatin adducts, has not been explored in Candida species yet. Here, we show that CaPolη plays a vital role in protecting Candida albicans genome from diverse array of DNA damaging agents, not limited to UV and cisplatin. Polη deficient strain did not exhibit any hyphal development in the presence of UV and cisplatin while the wild type strain profusely developed DNA damage induced filamentation. The polarized growth induced by HU and MMS was found to be Polη independent. No common regulatory pathway of morphogenesis operates in C. albicans due to genomic stress, rather Polη branches away from RAD53 dependent pathway to be specific to UV/cisplatin. Interestingly, serum that does not inflict any DNA damage also induces hyphal growth in C. albicans, and requires a functionally active Polη. Importantly, deletion of RAD30 sensitized the strain to amphotericin B; but its presence resulted in azole drug tolerance only in DNA damaging conditions. We suggest that the roles of CaPolη in genome stability and genotoxins induced filamentation are due to its TLS activities; whereas its TLS independent functions play a vital role in serum induced morphogenesis and amphotericin B resistance.
聚，一种独特的 TLS DNA 聚合酶，能促进 UV 诱导的 CPD 和顺铂加合物的有效绕过，尚未在念珠菌属中进行探索。在这里，我们表明 CaPolη 在保护白色念珠菌基因组免受多种 DNA 损伤剂的侵害方面起着至关重要的作用，不仅限于 UV 和顺铂。在存在 UV 和顺铂的情况下，缺乏 Polη 的菌株没有表现出任何菌丝发育，而野生型菌株则大量发育出 DNA 损伤诱导的丝状。发现 HU 和 MMS 诱导的极化生长与 Polη 无关。由于基因组应激，白色念珠菌中没有操作形态发生的共同调节途径，而是 Polη 分支脱离 RAD53 依赖途径，专门针对 UV/顺铂。有趣的是，即使不造成任何 DNA 损伤的血清也能诱导白色念珠菌的菌丝生长，并且需要功能活跃的 Polη。重要的是，RAD30 的缺失使该菌株对两性霉素 B 敏感；但它的存在仅在 DNA 损伤条件下导致唑类药物耐药。我们认为 CaPolη 在基因组稳定性和遗传毒素诱导的丝状形成中的作用是由于其 TLS 活性；而其 TLS 非依赖性功能在血清诱导的形态发生和两性霉素 B 耐药性中起着至关重要的作用。
