Replication-Independent ICL Repair: From Chemotherapy to Cell Homeostasis.

Interstrand crosslinks (ICLs) are a type of covalent lesion that can prevent transcription and replication by inhibiting DNA strand separation and instead trigger cell death. ICL inducing compounds are commonly used as chemotherapies due to their effectiveness in inhibiting cell proliferation. Naturally occurring crosslinking agents formed from metabolic processes can also pose a challenge to genome stability especially in slowly or non-dividing cells. Cells maintain a variety of ICL repair mechanisms to cope with this stressor within and outside the S phase of the cell cycle. Here, we discuss the mechanisms of various replication-independent ICL repair pathways and how crosslink repair efficiency is tied to aging and disease.

Transcription-Coupled Repair of DNA Interstrand Crosslinks by UVSSA.

DNA interstrand crosslinks (ICLs) are covalent bonds between bases on opposing strands of the DNA helix which prevent DNA melting and subsequent DNA replication or RNA transcription. Here, we show that Ultraviolet Stimulated Scaffold Protein A (UVSSA) participates in transcription-coupled repair of ICLs in human cells. Inactivation of UVSSA sensitizes human cells to ICL-inducing drugs, and delays ICL repair. UVSSA is required for transcription-coupled repair of a single ICL in a fluorescence-based reporter assay. UVSSA localizes to chromatin following ICL damage, and interacts with transcribing Pol II, CSA, CSB, and TFIIH. Specifically, UVSSA interaction with TFIIH is required for ICL repair. Finally, UVSSA expression positively correlates with ICL chemotherapy resistance in human cancer cell lines. Our data strongly suggest that transcription-coupled ICL repair (TC-ICR) is a bona fide ICL repair mechanism that contributes to crosslinker drug resistance independently of replication-coupled ICL repair.