DNA damage repair in colorectal cancer

ways DNA damage can be repaired

base excision repair, homologous recombination/non-homologous end joining, mismatch repair, nucleotide excision repair

consequence of accumulation of DNA damage

increased chance of activating an oncogene/deactivating tumour suppressor genes

base excision repair

glycosylase → endonuclease → polymerase → ligase

wrong base is detected, removed, hole is filled with correct base by polymerase and gap sealed by ligase

mechanism for mismatch repair

mismatch detected, removed (exonuclease), replaced by polymerase, ligases seals gap

nucleotide exicision repair mechanism

thymine dimer detected and dna opens up (helicase) to form bubble, damaged region removed, polymerase replaces and ligase seals.

double strand break repair mechanism: homologous recombination

cell cycle phase S/G2. end binding, processing and ligation

honhomologus end joining mechanism

cell cycle phase G0/G1. ku70/80, dna pk artemis, end binding, end processing and apposition and ligation.

colorectal cancer polyposis disorders

mans, map, nap, ppap

MAP

autosomal recessive missense mutations in MUTYH. increased cancer risk

MANS

autosomal recessive mutations in MBD4, increased risk of cancer

NAP

autosomal recessive nonsense mutations in NTHL1, increased risks of cancers

PPAP

autosomal dominant mutations in POLE and POLD1, increased risks of cancers. POLE/POLD1 essential for accurate DNA replication (proofread/remove mispaired bases)

lynch syndrome mutations

autosomal dominant mutations in MLH1, MSH2, MSH6, PMS2, increased risks of cancer

lynch syndrome repair mechanisms

repair enzymes MLH1, MSH2, MSH6, PMS2 remove mis paired bases (single bases or multiple mismatches)