Protein: DNA-dependent metalloprotease SPRTN (EC 3.4.24.-) (DNA damage protein targeting VCP) (DVC1) (Protein with SprT-like domain at the N terminus) (Spartan) (Q9H040)
Organism: Homo sapiens (Human)
Function: DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde. Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis. Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4. Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs (By similarity). SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (By similarity). Involved in recruitment of VCP/p97 to sites of DNA damage. Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation. Does not activate CHEK1 in response to DNA damage. May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis.
Subcellular location: Nucleus {ECO:0000269|PubMed:22681887, ECO:0000269|PubMed:22894931, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, ECO:0000269|PubMed:27852435}. Chromosome {ECO:0000269|PubMed:22894931, ECO:0000269|PubMed:22902628, ECO:0000269|PubMed:22987070, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:27852435, ECO:0000269|PubMed:27871365, ECO:0000269|PubMed:27871366, ECO:0000269|PubMed:31316063, ECO:0000269|PubMed:32649882}. Note=Localizes to sites of UV damage via the PIP-box (PubMed:22894931, PubMed:23042605). Recruited to stalled replication forks at sites of replication stress following deubiquitination (PubMed:22894931, PubMed:22987070, PubMed:23042605, PubMed:27871365, PubMed:32649882). CHEK1 stimulates recruitment to chromatin (PubMed:31316063). {ECO:0000269|PubMed:22894931, ECO:0000269|PubMed:22987070, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:27871365, ECO:0000269|PubMed:31316063, ECO:0000269|PubMed:32649882}.
Interaction partners:
- Proliferating cell nuclear antigen
- Transitional endoplasmic reticulum ATPase
- Polyubiquitin-C
- Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha
- Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta
- Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase TPTE2
- Putative tyrosine-protein phosphatase TPTE
- Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
- E3 ubiquitin-protein ligase RAD18
- Ubiquitin recognition factor in ER-associated degradation protein 1
Sequence:
MDDDLMLALRLQEEWNLQEAERDHAQESLSLVDASWELVDPTPDLQALFVQFNDQFFWGQLEAVEVKWSVRMTLCAGICSYEGKGGMCSIRLSEPLLKLRPRKDLVETLLHEMIHAYLFVTNNDKDREGHGPEFCKHMHRINSLTGANITVYHTFHDEVDEYRRHWWRCNGPCQHRPPYYGYVKRATNREPSAHDYWWAEHQKTCGGTYIKIKEPENYSKKGKGKAKLGKEPVLAAENKDKPNRGEAQLVIPFSGKGYVLGETSNLPSPGKLITSHAINKTQDLLNQNHSANAVRPNSKIKVKFEQNGSSKNSHLVSPAVSNSHQNVLSNYFPRVSFANQKAFRGVNGSPRISVTVGNIPKNSVSSSSQRRVSSSKISLRNSSKVTESASVMPSQDVSGSEDTFPNKRPRLEDKTVFDNFFIKKEQIKSSGNDPKYSTTTAQNSSSSSSQSKMVNCPVCQNEVLESQINEHLDWCLEGDSIKVKSEESL