USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repair and Prevent Tumors.

Ying Zhang,Syota Matsumoto,Paul J Galardy,Wim Vermeulen,Imke K Mandemaker,Oded Foreman,Christopher P Holland,Jurgen A Marteijn,Kaoru Sugasawa,Whitney R Lloyd

doi:10.3389/fcell.2021.663411

Ying Zhang, Syota Matsumoto + Show 8 more

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https://doi.org/10.3389/fcell.2021.663411

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Nucleotide excision repair (NER) is a pathway involved in the repair of a variety of potentially mutagenic lesions that distort the DNA double helix. The ubiquitin E3-ligase complex UV-DDB is required for the recognition and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) lesions through NER. DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation. DDB2 must remain on damaged chromatin, however, for sufficient time to recruit and hand-off lesions to XPC, a factor essential in the assembly of downstream repair components. Here we show that the tumor suppressor USP44 directly deubiquitinates DDB2 to prevent its premature degradation and is selectively required for CPD repair. Cells lacking USP44 have impaired DDB2 accumulation on DNA lesions with subsequent defects in XPC retention. The physiological importance of this mechanism is evident in that mice lacking Usp44 are prone to tumors induced by NER lesions introduced by DMBA or UV light. These data reveal the requirement for highly regulated ubiquitin addition and removal in the recognition and repair of helix-distorting DNA damage and identify another mechanism by which USP44 protects genomic integrity and prevents tumors.

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Maintenance of the accuracy of encoded genetic information is essential to guard the integrity of genomic identity across cell division and organism reproduction
Compared to wild-type cells, Usp44 null Murine embryonic fibroblasts (MEFs) repaired 6-4 photoproducts (6-4PPs) with normal kinetics, but had a selective defect in the repair of Cyclobutane pyrimidine dimers (CPDs). Consistent with this finding; we observed strong continued CPD immunostaining of Usp44 null MEFs 24-h after UVC exposure— a time when most damage has been repaired in wild-type cells (Figure 1C)
By combining these alleles we generated a series of mice predicted to have graded expression of USP44 and we examined CPD repair in MEFs derived from these animals

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Maintenance of the accuracy of encoded genetic information is essential to guard the integrity of genomic identity across cell division and organism reproduction. UV-DDB, cannot recruit the downstream TFIIH complex that is required to coordinate strand excision To accomplish this DDB2 forms a direct complex with XPC after binding to CPDs (Fitch et al, 2003; Sugasawa et al, 2005; Fei et al, 2011; Matsumoto et al, 2015). DDB2 forms a direct complex with XPC after binding to CPDs (Fitch et al, 2003; Sugasawa et al, 2005; Fei et al, 2011; Matsumoto et al, 2015) Both DDB2 and XPC are substrates of the Ub ligase activity of UV-DDB with differing results. The result of the ubiquitination event is the “pass-off ” of CPDs from DDB2 to XPC, which recruits the TFIIH complex. This model, leaves open the question of how DDB2 ubiquitination and degradation is prevented to allow time for XPC recruitment

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