The UVSSA protein is part of a genome integrity homeostasis network with links to transcription-coupled DNA repair and ATM signaling

Abstract

Significance Transcription-coupled repair (TCR) involves four core proteins: CSA, CSB, USP7, and UVSSA. CSA and CSB are mutated in the severe human neurocutaneous disease Cockayne syndrome. In contrast UVSSA is a mild photosensitive disease in which a mutated protein sequence prevents recruitment of USP7 protease to deubiquitinate and stabilize CSB. We deleted the UVSSA protein using CRISPR-Cas9 in an aneuploid cell line, HEK293, and determined the functional consequences. The knockout cell line was sensitive to transcription-blocking lesions but not sensitive to oxidative agents or PARP inhibitors, unlike CSB. Knockout of UVSSA also activated ATM, like CSB, in transcription-arrested cells. The phenotype of UVSSA, especially its rarity, suggests that many TCR-deficient patients and tumors fail to be recognized clinically.

Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells

“…3 B). DNA repair genes that protect against mutagenesis and chromosomal instability, such as Shprh 21 and Macrod2 22 , were upregulated, whereas those that support cell survival, cancer development, and resistance to DNA damage agents, such as Kdm2a 23 , 24 , Tlk2 25 , and Uvssa 26 , were downregulated (Fig. 3 C).…”

“…Among the top downregulated genes, Kdm2a participates in cell survival or immortality 23 , 24 . Uvssa -knockout cells are sensitive to UV and cisplatin 26 . TLK2 inhibition suppresses the growth of several cancers 38 , 39 .…”