Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Table 1

Summary of aberrations of the DDR pathways and their subsequent effects.

DNA repair protein	Mutation or polymorphism	Effect	Reference
OGG1	Ser 326 Cys	Increased risk of HCC.	[112]
XRCC1	Arg 280 His	Increased susceptibility to HBV infection.	[112]
	Arg 399 Gln	Increased risk of HCC.	[111]
	Arg 194 Trp and Arg 280 His	Increased risk of bladder cancer.	[240]
TP53	Arg 273 His, Arg 175 His, and Cys 135 Tyr	TP53 GOF mutants stimulate EMT features through binding to and transrepressing the promoter of miR-130b in endometrial cancer cells.	[241]
	Arg 248 Trp	TP53 GOF mutant interacts with the nuclease Mre11 and suppresses the loading of the MRN complex to DNA DSB, subsequently impairing the activation of ATM.	[124]
	Alteration of protein residues in a.a. 302–320	Retained associate with topoisomerase I and induced its activity during times of DNA stress in a regulated fashion, facilitating DNA repair. Suggested to lead to inappropriate topoisomerase I activity, resulting in an increase in recombinogenic events.	[242]
PARP-1	Val 762 Ala	Depressed PARP-1 activity is related to increased risk of cervical cancer, smoking-related lung cancer, and prostate cancer susceptibility.	[154, 155, 243]
Mre11	C 1714 T	Mutant Mre11 found at codon 1714C→T, which encodes a prematurely truncated protein, is suggested to be eliminated by NMD.	[244]
Rad50	Ser 635 Gly	Rad50 phosphosite-specific mutant supported normal activation of ATM in Rad50-deficient cells but failed to correct radiosensitivity, DNA DSB repair, and an S-phase checkpoint defect in Rad50-deficient cells.	[245]
	Hook domain replace with six a.a. residues from 684 to 689: Asn-Ala-Ala-Ile-Arg-Ser	Rad50 zinc hook mutant leads to MRN complex which failed to load to chromosomal DSB and exhibits very limited recruitment of DNA repair proteins.	[246]
Nbs1	657del5	The Nbs1  657del5 founder allele is associated with an increased risk of breast cancer.	[247]
	Ser 706 X	Results in a premature stop at codon 706 and a truncated Nbs1 protein that lacks the extreme C-terminal ATM recruitment motif (ARM).	[248]
ATM	Ser 367 Ala and Ser 2996 Ala	Both the S367A and S2996A mutants were defective in correcting radioresistant DNA synthesis in A-T cells.	[249]
	Ser 1893 Ala	Defective activation of ATM was manifested as defective substrate phosphorylation of TP53, Chk2, Nbs1, and SMCI in A-T cells transfected with ATM S1893A mutant failed to correct radiosensitivity, radiation-induced chromosome aberrations, and the defective G2/M checkpoint.	[250]
	Ser 1981 Ala	ATM is sequestered with a dimer or multimer with its kinase domain bound to an internal domain of a neighbouring ATM molecule containing serine 1981. A mutation occurs at autophosphorylation site, which leads to ATM unable to be released from other ATM molecules, and fails to phosphorylate other cellular substrates while DNA is damaged.	[251]