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Dennis A. Simpson
University of North Carolina at Chapel Hill
Cell cycle checkpointDNA damageMolecular biologyG2-M DNA damage checkpointBiology
56Publications
20H-index
1,325Citations
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Publications 49
Newest
#1Rashmi Kumar (UNC: University of North Carolina at Chapel Hill)H-Index: 14
#2Hui Xiao Chao (UNC: University of North Carolina at Chapel Hill)H-Index: 6
Last. Jeremy E. Purvis (UNC: University of North Carolina at Chapel Hill)H-Index: 16
view all 11 authors...
TP53 mutations in cancer are associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Here, we show that p53-deficient cells exhibit hyperactive repair of therapy-induced DNA double strand breaks (DSBs), which is suppressed by inhibition of DNA-dependent protein kinase (DNA-PK). Single-cell analyses of DSB repair kinetics and cell cycle state transitions reveal an es...
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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: 20
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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#1Wanjuan Feng (UNC: University of North Carolina at Chapel Hill)H-Index: 3
#2Dennis A. Simpson (UNC: University of North Carolina at Chapel Hill)H-Index: 20
Last. Gaorav P. Gupta (UNC: University of North Carolina at Chapel Hill)H-Index: 18
view all 12 authors...
Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (...
9 CitationsSource
#2Dennis A. SimpsonH-Index: 20
Last. Gaorav P. GuptaH-Index: 18
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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#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: 20
Last. Gaorav P. Gupta (UNC: University of North Carolina at Chapel Hill)H-Index: 18
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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#1Jacquelyn J. Bower (UNC: University of North Carolina at Chapel Hill)H-Index: 9
#2Leah D. Vance (UNC: University of North Carolina at Chapel Hill)H-Index: 1
Last. William K. Kaufmann (UNC: University of North Carolina at Chapel Hill)H-Index: 43
view all 9 authors...
Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patt...
8 CitationsSource
#2John J. McNulty (UNC: University of North Carolina at Chapel Hill)H-Index: 1
Last. William K. KaufmannH-Index: 43
view all 13 authors...
The objective of this study was to assess potential functional attenuation or inactivation of the intra-S checkpoint during melanoma development. Proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines were exposed to increasing fluences of UVC and intra-S checkpoint responses were quantified. Melanocytes displayed stereotypic intra-S checkpoint responses to UVC qualitatively and quantitatively equivalent to those previously demonstrated in skin fibroblasts. In compariso...
2 CitationsSource
#1Darmood WeiH-Index: 3
#2Aubri CharboneauH-Index: 3
Last. Bernard E. WeissmanH-Index: 14
view all 10 authors...
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#1Dennis A. SimpsonH-Index: 20
#2Nathalay Lemonie (UNC: University of North Carolina at Chapel Hill)H-Index: 1
Last. William K. KaufmannH-Index: 43
view all 5 authors...
The oncogenic BRAF(V600E) mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E) is not only clastogenic, but synergizes for clastogenesis caused by exposure to ultraviolet radiation in the 300 to 320 nM (UVB) range. Expression of BRAF(V600E) was associated with induction of Chk1 pS280 and a reduction in chromatin remodeling factors BRG1 a...
1 CitationsSource
#1Stephanie L. Smith-Roe (UNC: University of North Carolina at Chapel Hill)H-Index: 7
#2Jun NakamuraH-Index: 31
Last. Scott J. BultmanH-Index: 29
view all 10 authors...
// Stephanie L. Smith-Roe 1, 5 , Jun Nakamura 2 , Darcy Holley 1 , Paul D. Chastain II 3, 4 , Gary B. Rosson 1 , Dennis A. Simpson 3 , John R. Ridpath 3 , David G. Kaufman 3 , William K. Kaufmann 3 , Scott J. Bultman 1 1 Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 2 Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC, USA 3 Department of Pathology and Laboratory Medicine, Uni...
19 CitationsSource
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