Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.

Living organisms are continuously under threat from a vast array of DNA-damaging agents, which impact genome DNA. DNA replication machinery stalls at damaged template DNA. The stalled replication fork is restarted via bypass replication by translesion DNA-synthesis polymerases, including the Y-famil...

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Autores principales:	Yuriko Inomata, Takuya Abe, Masataka Tsuda, Shunichi Takeda, Kouji Hirota
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/69a7261294b9426e925c920d8a77b076
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spelling	oai:doaj.org-article:69a7261294b9426e925c920d8a77b0762021-12-02T20:11:10ZDivision of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.1932-620310.1371/journal.pone.0252587https://doaj.org/article/69a7261294b9426e925c920d8a77b0762021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252587https://doaj.org/toc/1932-6203Living organisms are continuously under threat from a vast array of DNA-damaging agents, which impact genome DNA. DNA replication machinery stalls at damaged template DNA. The stalled replication fork is restarted via bypass replication by translesion DNA-synthesis polymerases, including the Y-family polymerases Polη, Polι, and Polκ, which possess the ability to incorporate nucleotides opposite the damaged template. To investigate the division of labor among these polymerases in vivo, we generated POLη-/-, POLι-/-, POLκ-/-, double knockout (KO), and triple knockout (TKO) mutants in all combinations from human TK6 cells. TKO cells exhibited a hypersensitivity to ultraviolet (UV), cisplatin (CDDP), and methyl methanesulfonate (MMS), confirming the pivotal role played by these polymerases in bypass replication of damaged template DNA. POLη-/- cells, but not POLι-/- or POLκ-/- cells, showed a strong sensitivity to UV and CDDP, while TKO cells showed a slightly higher sensitivity to UV and CDDP than did POLη-/- cells. On the other hand, TKO cells, but not all single KO cells, exhibited a significantly higher sensitivity to MMS than did wild-type cells. Consistently, DNA-fiber assay revealed that Polη plays a crucial role in bypassing lesions caused by UV-mimetic agent 4-nitroquinoline-1-oxide and CDDP, while all three polymerases play complementary roles in bypassing MMS-induced damage. Our findings indicate that the three Y-family polymerases play distinctly different roles in bypass replication, according to the type of DNA damage generated on the template strand.Yuriko InomataTakuya AbeMasataka TsudaShunichi TakedaKouji HirotaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252587 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuriko Inomata Takuya Abe Masataka Tsuda Shunichi Takeda Kouji Hirota Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
description	Living organisms are continuously under threat from a vast array of DNA-damaging agents, which impact genome DNA. DNA replication machinery stalls at damaged template DNA. The stalled replication fork is restarted via bypass replication by translesion DNA-synthesis polymerases, including the Y-family polymerases Polη, Polι, and Polκ, which possess the ability to incorporate nucleotides opposite the damaged template. To investigate the division of labor among these polymerases in vivo, we generated POLη-/-, POLι-/-, POLκ-/-, double knockout (KO), and triple knockout (TKO) mutants in all combinations from human TK6 cells. TKO cells exhibited a hypersensitivity to ultraviolet (UV), cisplatin (CDDP), and methyl methanesulfonate (MMS), confirming the pivotal role played by these polymerases in bypass replication of damaged template DNA. POLη-/- cells, but not POLι-/- or POLκ-/- cells, showed a strong sensitivity to UV and CDDP, while TKO cells showed a slightly higher sensitivity to UV and CDDP than did POLη-/- cells. On the other hand, TKO cells, but not all single KO cells, exhibited a significantly higher sensitivity to MMS than did wild-type cells. Consistently, DNA-fiber assay revealed that Polη plays a crucial role in bypassing lesions caused by UV-mimetic agent 4-nitroquinoline-1-oxide and CDDP, while all three polymerases play complementary roles in bypassing MMS-induced damage. Our findings indicate that the three Y-family polymerases play distinctly different roles in bypass replication, according to the type of DNA damage generated on the template strand.
format	article
author	Yuriko Inomata Takuya Abe Masataka Tsuda Shunichi Takeda Kouji Hirota
author_facet	Yuriko Inomata Takuya Abe Masataka Tsuda Shunichi Takeda Kouji Hirota
author_sort	Yuriko Inomata
title	Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
title_short	Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
title_full	Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
title_fullStr	Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
title_full_unstemmed	Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.
title_sort	division of labor of y-family polymerases in translesion-dna synthesis for distinct types of dna damage.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/69a7261294b9426e925c920d8a77b076
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Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage.

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