David Livingston
· Emil Frei Professor of MedicineVerifiedHarvard University · Molecular and Cellular Biology
Active 1966–2023
About
David J. Livingston is a professor of Biological Chemistry and Molecular Pharmacology at Harvard University. His work has been central to guiding the Harvard Biochemical Sciences Tutorial Program for decades, including serving as Head Tutor from 1972 to 1996. His contributions emphasize the importance of learning how to think about scientific problems and how discoveries emerge from evidence, reflecting a focus on scientific thinking and evidence-based understanding. Livingston's role in the program highlights his dedication to fostering intellectual relationships between students and practicing scientists, mentoring students in scientific concepts, research papers, and career development. His long-standing involvement in the tutorial program underscores his commitment to undergraduate education in the life sciences and the development of future leaders in science.
Research topics
- Genetics
- Biology
- Cell biology
- Molecular biology
- Chemistry
- Computational biology
Selected publications
2023-03-31
preprintOpen access<p>Table S4: Somatic Sequence Alterations in parental tumor and xenograft DF101</p>
2023-04-03
preprintOpen accessSenior author<div>Abstract<p>BRCA1 promotes homologous recombination–mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and downmodulates its function. Moreover, RAP80 contains a poly-ADP-ribose–interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1–BRCA1–RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in <i>BRCA1<sup>+/+</sup></i> individuals.</p><p><b>Significance:</b> We propose a model that describes how BRCA1 functions to both support and restrict HRR. BRCA1 PARsylation is a key event in this process, failure of which triggers hyper-recombination and chromosome instability. Thus, hyperfunctioning BRCA1 can elicit genomic abnormalities similar to those observed in the absence of certain BRCA1 functions. <i>Cancer Discov; 4(12); 1430–47. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1355</p></div>
2023-03-31
preprintOpen access<p>Table S4: Somatic Sequence Alterations in parental tumor and xenograft DF101</p>
2023-04-03
preprintOpen accessSenior author<p>This file includes Supplementary Figures S1-S9. Figure S1. PARP1 is a partner of the RAP80-BRCA1 complex and promotes BRCA1 PARsylation. Figure S2. In vitro PARP1-driven PARsylation of BRCA1 fragments. Figure S3. Identification of a BRCA1 sequence required for optimal mono- and poly- ADP-ribosylation of the BRCA1 F3.7 fragment. Figure S4. The BRCA1 D5 sequence is not required for IRIF localization of BRCA1 in S/G2 phase nuclei. Figure S5. Olaparib treatment leads to increased BRCA1 chromatin association at sites near an I-SceI induced DSB. Figure S6. (a) RAP80 depletion and/or Olaparib treatment does not interfere with the interaction between BARD1 and BACH1, CtIP or RAD51. (b) The BRCA1-D5 sequence is required for a stable interaction between BRCA1 and RAP80 after IR, but not for the interaction between BRCA1 and BACH1 or CtIP. (c) RAP80 is not required for BRCA1 PARsylation in cells. (d) The RAP80-BRCA1 complex contains both PARsylated and unmodified BRCA1 molecules. Figure S7. PID is required for efficient RAP80 binding to PAR and PARsylated BRCA1, but not required for RAP80 IRIF localization. Figure S8. PARP1 activity is required for normal HRR tuning. Figure S9. Effects of RAD51 or EXO1/DNA2L depletion on STGC of cells expressing endogenous BRCA1, BRCA1-WT or BRCA1-D5, or depleted of BRCA1.</p>
Acta Geophysica · 2023-10-16
articleSenior author2023-03-31
preprintOpen access<p>Table S1: Optimal conditions for PDX luciferization; Table S3: BROCA characterization; Table S6: PIK3CA FISH. Figure S1: Schema for PDX generation; Figures S2: IHC of DF68; Figure S3: Array CGH of DF86; Figure S4: PI3K pathway analysis from RPPA; Figure S5: Correlation between BLI and plasma CA125</p>
2023-03-31
preprintOpen access<p>Table S2: Array CGH characterization of PDX models</p>
2023-04-03
preprintOpen accessSenior author<p>This file includes Supplementary Figures S1-S9. Figure S1. PARP1 is a partner of the RAP80-BRCA1 complex and promotes BRCA1 PARsylation. Figure S2. In vitro PARP1-driven PARsylation of BRCA1 fragments. Figure S3. Identification of a BRCA1 sequence required for optimal mono- and poly- ADP-ribosylation of the BRCA1 F3.7 fragment. Figure S4. The BRCA1 D5 sequence is not required for IRIF localization of BRCA1 in S/G2 phase nuclei. Figure S5. Olaparib treatment leads to increased BRCA1 chromatin association at sites near an I-SceI induced DSB. Figure S6. (a) RAP80 depletion and/or Olaparib treatment does not interfere with the interaction between BARD1 and BACH1, CtIP or RAD51. (b) The BRCA1-D5 sequence is required for a stable interaction between BRCA1 and RAP80 after IR, but not for the interaction between BRCA1 and BACH1 or CtIP. (c) RAP80 is not required for BRCA1 PARsylation in cells. (d) The RAP80-BRCA1 complex contains both PARsylated and unmodified BRCA1 molecules. Figure S7. PID is required for efficient RAP80 binding to PAR and PARsylated BRCA1, but not required for RAP80 IRIF localization. Figure S8. PARP1 activity is required for normal HRR tuning. Figure S9. Effects of RAD51 or EXO1/DNA2L depletion on STGC of cells expressing endogenous BRCA1, BRCA1-WT or BRCA1-D5, or depleted of BRCA1.</p>
2023-04-03
preprintOpen accessSenior author<div>Abstract<p>BRCA1 promotes homologous recombination–mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and downmodulates its function. Moreover, RAP80 contains a poly-ADP-ribose–interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1–BRCA1–RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in <i>BRCA1<sup>+/+</sup></i> individuals.</p><p><b>Significance:</b> We propose a model that describes how BRCA1 functions to both support and restrict HRR. BRCA1 PARsylation is a key event in this process, failure of which triggers hyper-recombination and chromosome instability. Thus, hyperfunctioning BRCA1 can elicit genomic abnormalities similar to those observed in the absence of certain BRCA1 functions. <i>Cancer Discov; 4(12); 1430–47. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 1355</p></div>
Data from 26th Pezcoller Symposium: Cancers Driven by Hormones
2023-03-30
preprintOpen access<div>Abstract<p>This symposium was held in Trento, Italy, on June 19–21, 2014, and was focused on advances in biology, physiology, and pathology of neoplasms affected by hormones, especially breast and prostate cancers. The stem cell function, the genetic and epigenetic interactions with hormones, the mechanisms of estrogen receptor transcription, biochemical markers and therapeutic targets in breast cancer, promotion of breast cancer carcinogenesis by progesterone, the basis for prostate cancer progression and the relevance of DNA repair processes, androgen receptor programming during prostate carcinogenesis, the metabolic stress role in tumor survival, and the diagnostic use of imaging in prostate cancer were discussed. <i>Cancer Res; 75(7); 1177–80. ©2015 AACR</i>.</p></div>
Recent grants
NIH · $73.2M · 2015
NIH · $7.0M · 2008
NIH · $6.8M · 2000
NIH · $1.7M · 2010
BRCA1 Function in Post-Damage Nuclear Foci
NIH · $4.6M · 2009–2020
Frequent coauthors
- 132 shared
Ralph Scully
Cancer Research Institute
- 69 shared
Richard Eckner
Rutgers, The State University of New Jersey
- 68 shared
Dennis C. Lynch
Harvard University
- 67 shared
James A. DeCaprio
Harvard University
- 66 shared
Andrew L. Kung
Memorial Sloan Kettering Cancer Center
- 64 shared
Ronny Drapkin
- 56 shared
I Bikel
Dana-Farber Cancer Institute
- 49 shared
Shridar Ganesan
Rutgers Cancer Institute of New Jersey
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