Table 3.
Disease-associated NBS 1 mutations.
| Mutation in NBS1 | Disease/Cancer Type | Location in the Structure | Effect on Structure/Function | Ref. |
|---|---|---|---|---|
| 657del5 | NBS; breast, prostate, and colorectal cancers; medulloblastoma; lymphoblastic leukemia; and non-Hodgkin lymphoma |
transition between BRCT1 and BRCT2 | Truncates NBS1 after BRCT1 and expresses a secondary C-terminal fragment starting near BRCT2. Disrupts tandem BRCT domains and proper phosphoprotein interaction. | [22,110] |
| V26I | medulloblastoma | FHA | Possibly disrupts phosphoprotein binding. | [62,116] |
| I41M | hepatocellular carcinoma | FHA | Possibly disrupts phosphoprotein binding | [61,117] |
| L57M/H711Y double mutation | medulloblastoma | FHA; C-terminus | L57M may disrupt the FHA/BRCT1 interface and destabilize the protein. H711Y may disrupt RNF20, MRE11, and/or ATM binding. |
[61,116] |
| T90S | intrahepatic cholangiocarcinoma | FHA | May disrupt FHA domain structure and/or phosphoprotein binding site. Decreased nuclear localization of MRE11. | [117] |
| S93L | acute lymphoblastic leukemia (ALL) | FHA | May disrupt FHA domain structure and/or phosphoprotein binding site. | [119] |
| D95N | ALL; breast, larynx, and prostate cancers | FHA | May disrupt FHA domain structure and/or phosphoprotein binding site. | [119,120,121,122] |
| T148I/ P427L double mutation | medulloblastoma | BRCT1; Intrinsically disordered region | T148I may disrupt the hydrophobic cluster where it is located and nearby phosphoserine binding cleft. | [116] |
| L150F | breast cancer | BRCT1 | Possible disruption of a hydrophobic cluster and phosphoserine binding cleft. Increases chromosomal instability. | [61,86,92] |
| I171V | ALL; breast, larynx, and colorectal cancers; head and neck tumors; aplastic anemia | BRCT1 | Possible disruption of a hydrophobic cluster and phosphoserine binding cleft. Increased sensitivity to IR and MMS and lower frequency of HR repair. Loss of association with MDC1. | [62,119,123,124,125,126] |
| E185Q | leukemia and lung cancers; urinary system cancer | BRCT1 | Possibly affects the interaction with BRCA1. May cause an increase in tumor aggression. | [120,127,128,129] |
| V210F | ALL and Non-Hodgkin lymphoma | BRCT1/BRCT2 linker | Hydrophobic residue could disrupt phosphoprotein binding and/or protein stability. | [62,119,130] |
| R215W | ALL; Hodgkin and Non-Hodgkin lymphomas; melanoma; prostate, breast, and colorectal cancers | BRCT1/BRCT2 linker | Disruption of salt bridge destabilizes structure. Decreased co-localization with γ-H2AX at sites of DNA damage and decreased repair efficiency. | [61,62,108,124,125,131] |
| D272N | hepatocellular carcinoma | BRCT2 | Could disrupt ATM phosphorylation of serine 278. | [111,117] |
| A308T | medulloblastoma | BRCT2 | May disrupt the structure of BRCT2 or interface between BRCT1/BRCT2. | [62,116] |
| G311R | medulloblastoma | BRCT2 | May disrupt the structure of BRCT2 or interface between BRCT1/BRCT2. | [62,116] |
| V348D | hepatocellular carcinoma | intrinsically disordered region | Could disrupt ATM phosphorylation of serine 343. | [117] |
| T402A | glioblastoma | intrinsically disordered region | Could disrupt ATM phosphorylation of serine 397. | [115] |
| S406F | glioblastoma | intrinsically disordered region | Could disrupt ATM phosphorylation of serine 397. May introduce order to the intrinsically disordered domain. | [115] |
| S415R | hepatocellular carcinoma | intrinsically disordered region | Could interrupt the sequence space of the intrinsically disordered domain, altering the surrounding structure. | [117] |
| M424V | glioblastoma | intrinsically disordered region | Unknown | [115] |
| T463I/ Q616H double mutation | glioblastoma | intrinsically disordered region | T463I could disrupt nuclear localization of MRE11; Q616H may affect ATM phosphorylation of serine 615. | [115] |
| T485M | glioblastoma | intrinsically disordered region | Unknown | [115] |
| F603L | hepatocellular carcinoma | C-terminal region | Could disrupt RAD18 binding. | [117] |
| S633T | hepatocellular carcinoma | C-terminal region | Could disrupt MRE11 binding. Deficient in nuclear localization of MRE11. | [117] |
| S638P | intrahepatic cholangiocarcinoma | C-terminal region | Could disrupt MRE11 binding. Deficient in nuclear localization of MRE11. | [117] |
| Y679H | renal cell carcinoma | C-terminal region | Could disrupt MRE11 binding and nuclear localization of MRE11. | [135] |