InterPro domain: IPR036590

The SRAP (SOS-response associated peptidase) family is characterised by the SRAP domain with a novel thiol autopeptidase activity, whose active site in human HMCES is comprised of the catalytic triad residues C2, E127, and H210 [ 1 ]. SRAP proteins are evolutionarily conserved in all domains of life. For instance, human HMCES and E. coli YedK are similar in both sequence and structure [ 2 ]. HMCES was originally identified as a possible reader of 5hmC in embryonic stem cell extracts using a double-stranded DNA molecule containing 5hmC as bait [ 3 ]. The bacterial members have operonic associations with the SOS DNA damage response, mutagenic translesion DNA polymerases, non-homologous DNA-ending-joining networks that employ Ku and an ATP-dependent ligase, and other repair systems [ 4 ].

Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. SRAP proteins shield the AP site from endonucleases and error-prone polymerases [ 5 ]. Both HMCES and YedK have been found to preferentially bind ssDNA and efficiently form DNA-protein crosslinks (DPCs) to AP sites in ssDNA. They crosslink to AP sites via a stable thiazolidine DNA-protein linkage formed with the N-erminal cysteine and the aldehyde form of the AP deoxyribose [ 6 ].

In B Cells, HMCES has also been shown to mediate microhomology-mediated alternative-end-joining through its SRAP domain [ 6 ].

This entry represents the SOS response associated peptidase (SRAP) superfamily.

1. HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells. Mol. Cell 77, 384-394.e4
2. Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link. Nat. Struct. Mol. Biol. 26, 613-618
3. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146-59
4. Novel autoproteolytic and DNA-damage sensing components in the bacterial SOS response and oxidized methylcytosine-induced eukaryotic DNA demethylation systems. Biol. Direct 8, 20
5. HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA. Cell 176, 144-153.e13