Cell undergoes numerous divisions during which DNA is replicated. Errors are often introduced during this replication process and need to be corrected. DNA repair enzymes play a crucial role in this repair process However, the mechanism by which the cell distinguishes its pre- and post-replicative stage have been hitherto unknown.
Researchers from the University of Copenhagen have solved the structure, and hence the function of TONSL-MMS22L DNA repair complex. This heterodimeric complex is essential for the stability of replication fork and DNA repair.
The team solved the structure of TONSL-MMS2L complex to 2.43 Å resolution. They found that the TONSL ARD (Ankyrin Repeat Domain) reads the histone domain specific for the unmethylated H4 tails at K20 (H4K20me0). They concluded that the ARD recognition domain of H4K20me0 helps to recruit TONSL to replication forks and post-replicative chromatin. These findings were published last month in a letter in the journal Nature.
The group, headed by Anja Groth at the Biotech Research and Innovation Centre, found that the new histones form a pre-deposition complex with MCM2 and ASF1, which finally combines with TONSL-MMS2L to be delivered to nascent chromatin. Using the structure, they propose that the TONSL acts like a histone chaperone as well as a histone reader. Acting like a histone chaperone, TONSL sequesters the H4 tail to prevent its spurious contact with DNA during H3-H4 deposition. In its role as a histone reader, TONSL binds with MMS2L to form a complex which accumulates at damaged forks and DNA lesions, and supports DNA repair via homologous recombination.
This study provides a new opportunity to understand the role of H4K20 in DNA repair. It complements the earlier known role of H4K20me1/2 in DNA repair via non-homologous end joining. The team wants to further investigate whether H4K20me0 influences the DNA repair pathway.
TONSL ARD is very similar in structure to the ARD of BARD1, which is required for BRCA1 tumour suppressor function and homologous recombination. This points to a role of H4K20me0 in tumour suppression, which leads to the possibility of a targeted cancer therapy in the future.
“Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy,” say the authors.
The article is based on the research paper published in the journal Nature.