The genome is under constant threat of damage from endogenous and exogenous agents, such as DNA replications errors, cell metabolic products, ionizing radiation, ultraviolet radiation (UV) and chemotherapy agents. The resulting DNA damages must be repaired timely to maintain genome stability, as errors can cause tumorigenesis, neurodegeneration, developmental abnormalities and other human diseases. To maintain genome integrity, cells have evolved a series of protection mechanisms to sense and repair DNA damages, termed DNA Damage Response.

Prof. GUO Caixia from Beijing Institute of Genomics of Chinese Academy of Sciences (CAS), and Prof. TANG Tieshan from Institute of Zoology of CAS revealed that translesion DNA synthesis (TLS) polymerase η is modified with O-linked β-N-acetylglucosamine (O-GlcNAc) at 457 threonine, termed O-GlcNAcylation.

After exposure to UV irradiation or cisplatin treatment, Polη is specifically recruited to replication forks to replace DNA replication polymerases for incorporating nucleotides opposite damaged DNA accurately. However, since Polη replicates undamaged DNA with a high error rate of 10^-2~10^-3, its recruitment and residence at replication forks has to be stringently regulated. So far, it remains a conundrum how disassembly of Polη happens after translesion DNA synthesis is completed.

Scientists revealed that T457A mutation does not impair Polη recruitment and bypass across DNA lesions. However, T457A mutation significantly attenuates Lys48 (K48)-linked Polη polyubiquitination at K462 catalyzed by Cullin 4-RING Ligase (CRL4)-DDB1-CDT2 (CRL4CDT2), and restrains p97-UFD1-NPL4 complex dependent Polη removal from replication forks, leading to an increased cellular mutation frequency and sensitivity to UV and cisplatin, accompanied with a reduced DNA replication rate.

This study unveiled an unexpected regulation between O-GlcNAcylation and ubiquitination of Polη and a pivotal role of O-GlcNAcylation in TLS polymerase switching. The expression level of Polη is significantly upregulated in many cancer cells, which is inversely correlated with cisplatin treatment efficacy.

It has added a further layer of regulation that elaborately controls TLS, genome stability and tumor chemoresistance in vivo, providing new strategies towards chemotherapy resistance and great promise for improving the survival of cancer patients.

The study was published online in Nature Communications and was supported in part by grants from the National Natural Science Foundation of China, and Ministry of Science and Technology.

A proposed model depicting the role of Polη O-GlcNAcylation in its removal after TLS (Image by GUO's lab)