MUTYH

1X51, 3N5N459570603ENSG00000132781ENSMUSG00000028687Q9UIF7Q99P21NM_001293190NM_001293191NM_001293192NM_001293195NM_001293196NM_012222NM_001350650NM_001350651NM_001159581NM_133250NM_001316747NP_001280119NP_001280120NP_001280121NP_001280124NP_001280125NP_036354NP_001337579NP_001337580NP_001280121.1NP_001280125.1NP_001153053NP_001303676NP_573513MUTYH (mutY DNA glycosylase) is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage. MUTYH (mutY DNA glycosylase) is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage. The protein is localized to the nucleus and mitochondria. Mutations in this gene result in heritable predisposition to colon and stomach cancer. Multiple transcript variants encoding different isoforms have been found for this gene. MUTYH has its locus on the short (p) arm of chromosome 1 (1p34.1), from base pair 45,464,007 to base pair 45,475,152 (45,794,835–45,806,142). The gene is composed of 16 exons and has a size of 546 amino acids and is approximately 7.1kb. The presence of disulfide crosslinking gives rise to a complex crystal structure of the MUTY-DNA. The protein structure of the MUTYH gene has its N-terminal on the 5’ and the C-terminal on the 3’. Within the N-terminal. There is an helix-hairpin-helix and pseudo helix-hairpin-helix contained within the N-terminal, in addition to and iron cluster motif Repair of oxidative DNA damage is the result of a collaborative effort of MUTYH, OGG1, and MTH1. MUTYH gene acts on the adenine base that have an A to 8-oxoG pairing while OGG1 (on chromosome 3 (3p26.2) part of the base excision repair pathway) detects and acts on 8-oxoG, thereby removing it. The resultant effect of the action of the genes results in correction of transversion mutations made by the incorrect G:C, T:A pairing.TP53 transcriptionally regulates MUTYH and it can be surmised that it may potentially act as a regulator for p53. MUTYH is overexpressed in CD4-T cells, the prostate, the colon and the rectum. There is evidence of MUTYH expression in kidney, intestinal, nervous system and muscle tissues. MUTYH has been shown to interact with Replication protein A1, PCNA and APEX1. The excision of the bases causes the formation of an apurinic/ apyrimidinic (AP site) gap. These gap sites are mutagenic in nature and require constant and immediate emendation and this is achieved by the active involvement of protein complexes that repair the AP gap site via short and long patch repair pathways. The short patch repair pathway employs POLB (DNA polymerase beta), APE1, XRCC1, PARP1 with the addition of either the LIG1 or LIG3 genes. When an insertion of one nucleotide occurs, the enzyme AP endonuclease (APEX/APE1) cuts out the mismatched base pairs at the AP site and this causes the evolvement of 5’dRP (5’ deoxyribose phosphate), a terminal blocking group, and 3’-OH ( 3’ hydroxyl end). POLB is required to remove the 5’dRP, and it does this by enzymatic activity, namely polymerase and dRP lyase. DNA ligase is used to seal the fragments after dRP excision causes the formation of 5’PO4 that is necessary to form the phosphodiester bonds of DNA. The purpose of PARP1 and XRCC1 in the single strand break repair pathway, is to stabilize the strands of DNA while they undergo repair, synthesis, gap-filling and ligation. PARP1 acts as a recruit agent for XRCC1. The nick sealing of the strands is accomplished by the formation of LIG1 (DNA ligase 1) and/or LIG3/ XRCCI complex that attach to processed end of the corrected strands and reinstate the original conformation of the strand.Long patch repair comes into play when more nucleotides are involved, ranging from 2 to 12. It is hypothesized that Polymerase ? (POLD) and Polymerase ? (POLE), assisted by the PCNA (proliferating cell nuclear antigen) in conjunction with replication factor C (RFC) that acts as a stabilizer and places newly synthesized nucleotides on the DNA strand. Both the polymerases repair the DNA by employing the strand displacement synthesis mechanism. This mechanism occurs downstream a DNA strand and the 5’ is transformed into a “flap intermediate” causing it to be “displaced”. FEN1 ( flap structure-specific endonuclease 1), a nuclease, removes the displaced strand and this results in a ligatable strand of DNA.Long patch repair, like short patch repair, includes the use of APE1 and PARP1 and LIG1.The repair pathway is partially determined by the amount of ATP present after the removal of the deoxyribose phosphate end. The long patch repair pathway is preferred under conditions of low ATP concentration while the short repair pathway is preferred under high concentrations of ATP. Other notable interactions include MUTYH and Replication protein A is a single strand binding protein that prevents the annealing of DNA during replication, it also plays a role as an activator for damage repair on DNA. There is a hypothetical relation between the interaction of Mismatch Repair proteins (MMR) such as MSH 2,3 and 6, MLH1, PMS1 and 2, and MUTYH in which the proposed result of their partnering is to increase susceptibility to cancer.