Table 2.

Disease-associated RAD50 mutations.

Mutation in RAD50	Disease/Cancer Type	Location in the Structure	Effect on Structure/Function	Ref.
D69N, D69Y, and D69G	uterine, colorectal, bladder, and lung cancers; myelodysplastic syndrome	Walker A	Impaired Tel1/ATM activation and decreased ATP hydrolysis. Could affect “open” to “closed” global transition dynamics.	[77]
R850C	endometrioid, breast/ovarian cancers	coiled coil region	Unknown	[95,96]
R1093Stop compound heterozyg-ous with Stop1313Y	NBSLD	truncated at C-terminal sub-domain	RAD50 deficiency. Increased radiosensitivity, chromosomal instability, impaired activation of ATM, impaired G1/S cellcycle-checkpoint activation.	[14]
R1214H and R1214C	pancreatic cancer	extended signature helix/basic switch	Impaired ATP hydrolysis activity, NBD association, and allostery within MRN.	[77,97,98,99]
A1229D	Burkitt Lymphoma	Walker B	Unknown	[100]
E1232K	lung cancer	Walker B	Defective in ATP hydrolysis.	[47,77]
N1236D	Burkitt Lymphoma	D-loop	Unknown	[100]
L1237F and L1237V	bladder and colorectal cancer; breast cancer	D-loop	Increased ATP hydrolysis. Destabilization of “closed” MRN complex. Loss of ATM signaling and Mre11 exonuclease activity.	[77,91,101]
D1238N	breast cancer	D-loop	Severe DSB repair defect. Increased ATP hydrolysis. Destabilization of “closed” MRN complex. Loss of ATM signaling and Mre11 exonuclease activity.	[91,101]
R1256C and R1256H	bladder/uterine cancers	between D-loop and His-loop	Impaired Tel1/ATM activation.	[77]
Q1259K	endometrial carcinoma	between D-loop and His-loop	Unknown	[101]
Q1263H	endometrial carcinoma	between D-loop and His-loop	Unknown	[95,96]