Table 1.

Disease-associated mutations in MRE11.

Mutation in MRE11	Disease/Cancer Type	Location in Gene or Structure	Effect on Structure/Function	Ref.
Δ5-7 MRE11	colon cancer	deletion of exons 5-7; deletes the third and fourth phosphoesterase motifs	Loss of 3′-to-5′ exonuclease activity impairs HR. Weak interactions with RAD50 and NBS1. Suppressed ATM activation.	[76]
E42K, E42D, and E42A	ovarian, uterine, and small cell lung cancers	nuclease domain	Inhibits Tel1/ATM activation. May disrupt an ionic interaction stabilizing the interface of the nuclease and capping domains.	[77]
S104C	Breast cancer	nuclease domain, NBS1 interaction region 2	Reduced NBS1 binding.	[57,78]
D113G	NBSLD	nuclease domain, NBS1 interaction region 2	May affect MRE11 dimer geometry/stability and NBS1 binding.	[58,79]
N117S	ATLD3/4	nuclease domain, NBS1 interaction region 2	May affect MRE11 dimer stability. Reduced NBS1 binding.	[12,80]
A177V	lung cancer	nuclease domain	Impairs DSB repair in yeast. Packing of this buried residue might be disrupted.	[77]
R202G	breast cancer	nuclease domain	Could affect the local stability around NBS1 binding region 1. Impaired NBS1 interaction.	[57,82]
W210C	ATLD7/8	nuclease domain	Affects MRN protein expression resulting in dysfunctional MRN complex.	[58,83]
W243R	ATLD17/18	nuclease domain	Impaired interactions with RAD50 and NBS1. Disrupts MRE11 dimerization. Causes defects in ATM activation.	[73,74,81]
F237C	breast cancer	nuclease domain	Unknown	[85]
H302Y	breast cancer	nuclease domain	Unknown	[85]
R305W	ovarian cancer	linker between nuclease and capping domains	Possibly affects structural organization of protein.	[57,86]
D368Y	lung and nasopharyn-geal cancers	capping domain	Strongly impairs DSB repair. Possibly disrupts the fold of MRE11.	[77]
L473F	colorectal cancers	helix-loop-helix	Impaired interaction with RAD50.	[84]
T481 Kcompound heterozyg-ous with R527Stop	ATLD5/6	helix-loop-helix	Decreased expression levels of MRN. Increased sensitivity to IR. Attenuated ATM activation.	[87]
R503H	breast carcinoma	helix-loop-helix	Unknown	[78]
R572Q	lymphoma	GAR motif	Disrupts interactions with RAD50 and NBS1. Defects in ATR activation.	[74,78]
R633Stop	ATLD1/2; breast cancer	truncation near C-terminus	Does not localize to sites of damage.	[12,74,80,82]