Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

Abstract

Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy.

A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1

“…In standard-of-care cancer therapies that involve platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can also bypass platinum-DNA adducts, negating the benefits of the treatment and enabling drug resistance [19][20][21][22][23][24][25][26][27]. Moreover, POLH has been implicated in resistance to nucleoside analogs, such as gemcitabine and cytarabine [28], and other studies suggest that POLH plays an important role in oxidative stress resistance, likely by carrying out the TLS [29,30] of bulky oxidative base lesions, such as cyclopurines [31][32][33]. Beyond its canonical TLS functions, recent studies found that POLH is important for resistance against the chemotherapeutic alkylating agent, temozolomide (TMZ), seemingly via a TLS-independent mechanism [34].…”

A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade

“…Further polyubiquitination of this ubiquitin moiety on PCNA is also possible and initiates an alternative pathway of template switching (reviewed in ( Branzei and Szakal, 2017 , 2016 ; Prado, 2018 ). Polyubiquitination of PCNA involves the heterodimeric E2 complex Mms2-Ubc13 and the E3 proteins HLTF or SHPRH; the polyubiquitin chain forms on ubiquitin’s K63 residue rather than K48, the former type triggering template switching and the latter recognition and degradation by the proteasome (reviewed in Gallo and Brown, 2019 ; Kanao and Masutani, 2017 ; Leung et al., 2018 ; Ripley et al., 2020 ; Wilkinson et al., 2020 ). What determines the “decision” of whether PCNA is simply monoubiquitinated or further polyubiquitinated with activation of TLS or template switching, respectively, is unclear.…”

Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

“…In addition to UV-induced DNA damage, POLH has been shown to bypass cisplatin adducts, as well as oxaliplatin adducts (8)(9)(10)(11)(12)(13)(14). Additional studies suggest that POLH may also play an important role in oxidative stress resistance, likely by carrying out translesion synthesis (TLS) (15,16) of bulky oxidative base lesions, such as cyclopurines (17)(18)(19).…”