Abstract
Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. Invitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio ofmutantto wild-type RAD51 in cells. Instead, patientcells aresensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 478-490 |
| Number of pages | 13 |
| Journal | Molecular Cell |
| Volume | 59 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 6 2015 |
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A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. / Wang, Anderson T.; Kim, Taeho; Wagner, John E.; Conti, Brooke A.; Lach, Francis P.; Huang, Athena L.; Molina, Henrik; Sanborn, Erica M.; Zierhut, Heather; Cornes, Belinda K.; Abhyankar, Avinash; Sougnez, Carrie; Gabriel, Stacey B.; Auerbach, Arleen D.; Kowalczykowski, Stephen C.; Smogorzewska, Agata.
In: Molecular Cell, Vol. 59, No. 3, 06.08.2015, p. 478-490.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination
AU - Wang, Anderson T.
AU - Kim, Taeho
AU - Wagner, John E.
AU - Conti, Brooke A.
AU - Lach, Francis P.
AU - Huang, Athena L.
AU - Molina, Henrik
AU - Sanborn, Erica M.
AU - Zierhut, Heather
AU - Cornes, Belinda K.
AU - Abhyankar, Avinash
AU - Sougnez, Carrie
AU - Gabriel, Stacey B.
AU - Auerbach, Arleen D.
AU - Kowalczykowski, Stephen C.
AU - Smogorzewska, Agata
PY - 2015/8/6
Y1 - 2015/8/6
N2 - Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. Invitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio ofmutantto wild-type RAD51 in cells. Instead, patientcells aresensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
AB - Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. Invitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio ofmutantto wild-type RAD51 in cells. Instead, patientcells aresensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
UR - http://www.scopus.com/inward/record.url?scp=84938579589&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938579589&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.07.009
DO - 10.1016/j.molcel.2015.07.009
M3 - Article
C2 - 26253028
AN - SCOPUS:84938579589
VL - 59
SP - 478
EP - 490
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -