van der Sluijs Roxanne V, Verkennis Alexander E E, Hodskinson Michael R, Barnett Jamie, Cruz Victoria M, Hernandez-Quiles Miguel, Liolios Themistoklis, Morton Sally B, Hendrikx Aiko, Bos Collin, Post Harm, Millington Christopher L, Rouillon Clément, Ricci Giulia, Mattiroli Francesca, Williams David M, Altelaar Maarten, Vermeulen Michiel, Patel K J, Knipscheer Puck
Oncode Institute, 3521 AL Utrecht, The Netherlands.
Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
Nucleic Acids Res. 2025 Sep 23;53(18). doi: 10.1093/nar/gkaf875.
DNA interstrand crosslinks (ICLs) are highly cytotoxic lesions that block essential cellular processes like replication and transcription. Endogenous ICLs can be induced by reactive aldehydes produced during normal cellular metabolism. Defective repair of these aldehyde-induced ICLs is associated with Fanconi anaemia (FA), a cancer predisposition syndrome. We previously showed that acetaldehyde-induced ICLs are repaired by the FA pathway and a novel excision-independent pathway. Here, we demonstrate that ICLs induced by acrolein, another cellular aldehyde, are also repaired by both pathways, establishing the generality of aldehyde ICL repair. Focusing on the FA pathway, we identify DNA polymerase kappa (Polκ) as the primary translesion synthesis (TLS) polymerase responsible for the insertion step during lesion bypass of unhooked aldehyde ICLs. This function requires Polκ's catalytic activity and PCNA interaction domains but is independent of Rev1 interaction. In contrast, Polκ has a non-catalytic role in the extension step of cisplatin ICL repair that is dependent on Rev1 interaction. Our work reveals a key role for Polκ in aldehyde ICL repair and provides mechanistic insights into how different ICL structures determine the choice of TLS polymerases during repair.
DNA链间交联（ICLs）是具有高度细胞毒性的损伤，会阻断复制和转录等基本细胞过程。内源性ICLs可由正常细胞代谢过程中产生的反应性醛类诱导产生。这些醛类诱导的ICLs修复缺陷与范可尼贫血（FA）相关，FA是一种癌症易感综合征。我们之前表明，乙醛诱导的ICLs可通过FA途径和一种新的不依赖切除的途径进行修复。在此，我们证明由另一种细胞醛类丙烯醛诱导的ICLs也可通过这两种途径进行修复，从而确定了醛类ICLs修复的普遍性。聚焦于FA途径，我们确定DNA聚合酶κ（Polκ）是负责在未钩连的醛类ICLs损伤绕过过程中插入步骤的主要跨损伤合成（TLS）聚合酶。该功能需要Polκ的催化活性和PCNA相互作用结构域，但不依赖于Rev1相互作用。相比之下，Polκ在顺铂ICLs修复的延伸步骤中具有非催化作用，该作用依赖于Rev1相互作用。我们的工作揭示了Polκ在醛类ICLs修复中的关键作用，并为不同ICL结构如何在修复过程中决定TLS聚合酶的选择提供了机制性见解。
