DNA repair mechanisms M2C

exogenous agents

originate externally, radiation, pollutants, chemical carcinogens

endogenous agents

produced internally, ROS, RNS, depurination, depyrimidation, deamination

dysfunctional DNA damage response causes:

cancer

not all mutagens cause the same ______.

mutations

DNA replications stress → base mismatches → ins/dels→

mismatch repair

oxygen radicals/ionizing radiation/chemotherapeutics → ssDNA breaks, Abasic sites, 8-oxoguanine →

base-excision repair

UV light, polyaromatic hydrocarbons → DNA adducts, INTRAstrand crosslinks →

nucleotide-excision repair → transcription-coupled/global genome repair

ionizing radiation, chemotherapeutics → dsDNA breaks, INTERstrand crosslinks →

dsDNA break repair → homologous recombination/non-homologous end-joining

DDR: alert-

DNA damage sensor proteins

DDR: respond-

proteins act as signal transducers and mediators to the repair machinery

DDR: result-

effector pathways include DNA repair, cell cycle arrest, senescence, apoptosis

corrects erroneous base pairing

mismatch repair

deficient _____ leads to microsatellite instability (MSI) and accumulation of point mutations (common in repeat nucleotide sequences)

mismatch repair

occurs at double strand breaks or when DNA damage causes gap in synthesis during DNA replication, strands of a normal sister chromatids are used to repair a damaged sister chromatid

homologous recombination repair

mutation in ATM gene →

failure to repair DNA damage

repair used when cells exposed to UV light

nucleotides excision repair (NER): enzymes cut damaged region out of bubble, DNA pol replaces DNA

NER goes wrong

Xeroderma pigmentosum

DNA damage response includes:

sensors, signaling, and effectors

DNA damage may result in:

• cell cycle arrest: senesce, DNA repair

• apoptosis

• cancer and other diseases

mismatch repair

lynch syndrome

double strand break repair

fanconi anemia and ataxia telangiectasia