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John H.J. Petrini
Memorial Sloan Kettering Cancer Center
DNA repairDNA damageMolecular biologyGeneticsBiology
123Publications
54H-index
13.2kCitations
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Publications 121
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#1Katerina D. Fagan-Solis (UNC: University of North Carolina at Chapel Hill)H-Index: 1
#2Dennis A. Simpson (UNC: University of North Carolina at Chapel Hill)H-Index: 19
Last. Joel S. Parker (UNC: University of North Carolina at Chapel Hill)H-Index: 77
view all 13 authors...
Summary The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hyp...
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#1Sarem Hailemariam (UW: University of Washington)H-Index: 1
#1Sarem HailemariamH-Index: 1
Last. Peter M. J. BurgersH-Index: 66
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1 CitationsSource
#1Marcel Hohl (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 7
#2Aditya Mojumdar (U of C: University of Calgary)H-Index: 2
Last. John H.J. Petrini (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 54
view all 12 authors...
The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with ...
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#1Aditya Mojumdar (U of C: University of Calgary)
#2Kyle Sorenson (U of C: University of Calgary)H-Index: 1
Last. Jennifer A. Cobb (U of C: University of Calgary)H-Index: 7
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Summary Non-homologous end joining (NHEJ) and homologous recombination (HR) are the two major pathways of DNA double-strand break (DSB) repair and both are highly conserved from yeast to mammals. Nej1 has a role in DNA end-tethering at a DSB, and the Mre11/Rad50/Xrs2 (MRX) complex is important for its recruitment to the break. Nej1 and Dna2-Sgs1 interact with the C-terminal end of Mre11, which also includes the region where Rad50 binds. By characterizing the functionality of Nej1 in two rad50 mu...
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#1Jun Hyun Kim (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 3
#2Alexander Penson (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 10
Last. John H.J. Petrini (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 54
view all 4 authors...
We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11−Rad50 core of the Mre11 complex. The Nbnmid8 allele was expressed exclusively in hematopoietic lineages (in Nbn−/mid8vav mice). Unlike Nbnflox/floxvav mice with Nbn deficiency in the bone marrow, Nbn−/mid8vav mice were viable. Nbn−/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blocka...
1 CitationsSource
#1Jun Hyun Kim (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 3
#2Alexander Penson (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 10
Last. John H.J. Petrini (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 54
view all 4 authors...
We derived a mouse model in which a mutant form of Nbs1 (Nbs1mid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbs1mid8 allele was expressed exclusively in hematopoietic lineages (in Nbs1-/mid8vav mice). Unlike Nbs1flox/floxvav mice, which are Nbs1 deficient in the bone marrow, Nbs1-/mid8vav mice were viable. Nbs1-/mid8vav hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage specific blockage of B cel...
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#2Dennis A. SimpsonH-Index: 19
Last. Gaorav P. GuptaH-Index: 17
view all 7 authors...
Defects in the DNA damage repair system result in increased genomic instability and have recently been implicated as being drivers of tumorigenesis in both familial and sporadic breast cancers. To maintain genomic integrity, cells have a DNA damage response (DDR) mechanism that functions to repair damaged DNA efficiently and commits cells to death if damage is irreparable. Failure of this mechanism results in genomic instability and cancer predisposition. Widespread chromosomal instability is a ...
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#1Guochang HuangH-Index: 6
#2Andrew KaufmanH-Index: 10
Last. Bhuvanesh SinghH-Index: 62
view all 13 authors...
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#1Katerina D. Fagan-Solis (UNC: University of North Carolina at Chapel Hill)H-Index: 1
#2Dennis A. Simpson (UNC: University of North Carolina at Chapel Hill)H-Index: 19
Last. Gaorav P. Gupta (UNC: University of North Carolina at Chapel Hill)H-Index: 17
view all 6 authors...
Chromosomal rearrangements and copy number aberrations are a major mechanism for driver gene alterations in breast cancer. However, the origins of chromosomal instability during breast tumorigenesis are poorly understood. We have recently shown that oncogene expression in normal mammary epithelial cells induces replication stress and a DNA damage response (DDR). The double-strand break sensor Mre11 is required for the oncogene-induced DDR, and suppression of Mre11 is sufficient to promote the de...
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#1Anton G. HenssenH-Index: 7
#2Casie Reed (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 9
Last. Alex Kentsis (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 29
view all 17 authors...
Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5 , that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we disco...
10 CitationsSource
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