- Email: [email protected]
Stephen Elledge and the DNA damage response
DNA Repair 35 (2015) 156–157
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Stephen Elledge and the DNA damage response David Cortez a,∗ , Zheng Zhou b , Yolanda Sanchez c,d a
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States c Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, United States d Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, United States b
Stephen J. Elledge, Gregor Mendel Professor of Genetics at Harvard Medical School, is co-recipient of the 2015 Albert Lasker Basic Medical Research Award for his studies on the mechanisms of the DNA damage response (DDR) in eukaryotic cells. The DNA in every cell in our body is damaged thousands of times each day. Dr. Elledge’s research in the past 20 years has elucidated the mechanisms that sense this damage and signal to protect the cell and organism from death and disease. The DDR regulates cell cycle checkpoints, mobilizes DNA repair activities, and controls cell fate outcomes such as apoptosis. Elledge’s studies on the DDR started with his observation as a post-doctoral fellow in Ronald Davis’ lab at Stanford that subunits of the budding yeast ribonucleotide reductase enzyme, responsible for the rate-limiting step in deoxyribonucleotide synthesis, are transcriptionally activated in response to DNA damage [1]. This discovery suggested to Elledge that there must be a signaling pathway communicating the presence of DNA damage to the transcriptional machinery. As a geneticist, he also suggested a potential way to identify genes encoding DDR proteins through a transcriptional reporter assay. Indeed, after he started his own laboratory at Baylor College of Medicine, his first student, Zheng Zhou, established a reporter that made it feasible to isolate mutations in DDR genes including DUN1 [2]. Importantly, Elledge and colleagues showed that Dun1 is a kinase cementing the idea that the DDR is a signaling pathway. By employing a series of genetic tricks, Elledge identified and characterized additional DDR signaling proteins in yeast including another kinase Rad53 [3]. By this time, Elledge had begun recruiting post-doctoral fellows to the lab that were trained in utilizing higher eukaryotic systems. Furthermore, his lab worked in close proximity and collaboration with Dr. Wade Harper who employed biochemical approaches to studying cell regulatory pathways. Thus, with an expanding tool-bag of approaches, Elledge expanded his discoveries into human and mouse systems.
∗ Corresponding author. Phone: 615 322 8547; Fax: 615 343 0704. E-mail address: [email protected] (D. Cortez). http://dx.doi.org/10.1016/j.dnarep.2015.11.001 1568-7864/© 2015 Published by Elsevier B.V.
Elledge discovered that the functional orthologues of the Rad53 kinase in mammalian cells were CHK1 and CHK2, defined mechanisms by which these kinases are activated by the upstream kinases ATR and ATM, and described how they signal to control cell cycle progression and other DDR responses [4–7]. He then turned his attention to how the damage sensing system works. Since ATR can be activated by many forms of DNA damage and by agents that stall DNA replication, the signal that ATR sensed needed to be something that all of these genotoxic stresses had in common. Elledge’s identification of a partner protein for ATR called ATRIP paved the way for his discovery that ATRIP serves as the sensor of single-stranded DNA through an interaction with the single-stranded DNA binding protein RPA [8,9]. As a post-doctoral fellow in the laboratory while these discoveries were being made, I can attest to the excitement and energy that made the lab such a fun place to work. No spare time was too short to fill with science. As Elledge went through the lab on the way out for the evening he would often say, “Walk with me” to discuss one last item on the way to the elevators. Two other postdocs, Yoli Sanchez and Jeff Bachant recall that Elledge often called the lab late in the evening to learn about new data or just talk ideas. Often he seemed to be speaking in a whisper as if he didn’t want to get caught by his family. As Bachant recalls, “Steve led the lab with something of a subdued ferocity. He pumped his ideas into it, and knew how to use the strengths of the group to get things done. He could bring people together and make things happen very quickly, and he also knew how to give people free reign to push into new areas.” Elledge set a high standard for his trainees and expected a high degree of independence. However, he cared about every project, and the resources and ideas were never limiting. He had a knack for identifying the key question or experiment, and he also found a way to make everyone in the lab productive. The lab atmosphere was a direct reflection of Elledge’s personality. His own words capture it best, “You are only as good as your next paper.” Elledge’s scientific contributions have since expanded to span many fields from ubiquitin-dependent proteolysis to cancer. A common theme is the development of new technologies and approaches. Elledge can be rightfully described as scientist and
D. Cortez et al. / DNA Repair 35 (2015) 156–157
engineer. He often seems most happy when he is devising new technologies or making them more useful. For many years the yeast two-hybrid strains and cDNA libraries he distributed freely were the best available empowering many investigators in many fields. He developed an early version of recombination-based cloning vectors and later developed methodologies and reagents for performing RNA interference screens in mammalian cells. Of course, Elledge’s work happened in the context of a rich and diverse research field with many investigators working to explain DDR mechanisms. There are too many people to acknowledge, but many key discoveries were made in other labs and the competition between labs spurred the rapid evolution of the field. We now know that there are hundreds of proteins that function in the DDR to maintain genome integrity. While the cataloguing of DDR proteins that Elledge started is likely nearing completion, the field will be busy for many decades deciphering DDR mechanisms, understanding the consequences for human disease when it doesn’t work, and understanding how we can intervene in these circumstances. Undoubtedly Elledge will continue to lead these endeavors in his own ongoing research, by creating new technologies to the benefit of everyone, and through his many trainees that have their own laboratories.
157
References [1] S.J. Elledge, R.W. Davis, Identification and isolation of the gene encoding the small subunit of ribonucleotide reductase from Saccharomyces cerevisiae: DNA damage-inducible gene required for mitotic viability, Mol. Cell. Biol. 7 (1987) 2783–2793. [2] Z. Zhou, S.J. Elledge, DUN1 encodes a protein kinase that controls the DNA damage response in yeast, Cell 75 (1993) 1119–1127. [3] J.B. Allen, Z. Zhou, W. Siede, E.C. Friedberg, S.J. Elledge, The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast, Genes Dev. 8 (1994) 2401–2415. [4] Y. Sanchez, C. Wong, R.S. Thoma, R. Richman, Z. Wu, H. Piwnica-Worms, S.J. Elledge, Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25, Science 277 (1997) 1497–1501. [5] S. Matsuoka, M. Huang, S.J. Elledge, Linkage of ATM to cell cycle regulation by the Chk2 protein kinase, Science 282 (1998) 1893–1897. [6] Q. Liu, S. Guntuku, X.S. Cui, S. Matsuoka, D. Cortez, K. Tamai, G. Luo, S. CarattiniRivera, F. DeMayo, A. Bradley, L.A. Donehower, S.J. Elledge, Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint, Genes Dev. 14 (2000) 1448–1459. [7] Y. Sanchez, J. Bachant, H. Wang, F. Hu, D. Liu, M. Tetzlaff, S.J. Elledge, Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms, Science 286 (1999) 1166–1171. [8] D. Cortez, S. Guntuku, J. Qin, S.J. Elledge, ATR and ATRIP: partners in checkpoint signaling, Science 294 (2001) 1713–1716. [9] L. Zou, S.J. Elledge, Sensing DNA damage through ATRIP recognition of RPAssDNA complexes, Science 300 (2003) 1542–1548.
Contents lists available at ScienceDirect
DNA Repair journal homepage: www.elsevier.com/locate/dnarepair
Stephen Elledge and the DNA damage response David Cortez a,∗ , Zheng Zhou b , Yolanda Sanchez c,d a
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States c Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, United States d Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, United States b
Stephen J. Elledge, Gregor Mendel Professor of Genetics at Harvard Medical School, is co-recipient of the 2015 Albert Lasker Basic Medical Research Award for his studies on the mechanisms of the DNA damage response (DDR) in eukaryotic cells. The DNA in every cell in our body is damaged thousands of times each day. Dr. Elledge’s research in the past 20 years has elucidated the mechanisms that sense this damage and signal to protect the cell and organism from death and disease. The DDR regulates cell cycle checkpoints, mobilizes DNA repair activities, and controls cell fate outcomes such as apoptosis. Elledge’s studies on the DDR started with his observation as a post-doctoral fellow in Ronald Davis’ lab at Stanford that subunits of the budding yeast ribonucleotide reductase enzyme, responsible for the rate-limiting step in deoxyribonucleotide synthesis, are transcriptionally activated in response to DNA damage [1]. This discovery suggested to Elledge that there must be a signaling pathway communicating the presence of DNA damage to the transcriptional machinery. As a geneticist, he also suggested a potential way to identify genes encoding DDR proteins through a transcriptional reporter assay. Indeed, after he started his own laboratory at Baylor College of Medicine, his first student, Zheng Zhou, established a reporter that made it feasible to isolate mutations in DDR genes including DUN1 [2]. Importantly, Elledge and colleagues showed that Dun1 is a kinase cementing the idea that the DDR is a signaling pathway. By employing a series of genetic tricks, Elledge identified and characterized additional DDR signaling proteins in yeast including another kinase Rad53 [3]. By this time, Elledge had begun recruiting post-doctoral fellows to the lab that were trained in utilizing higher eukaryotic systems. Furthermore, his lab worked in close proximity and collaboration with Dr. Wade Harper who employed biochemical approaches to studying cell regulatory pathways. Thus, with an expanding tool-bag of approaches, Elledge expanded his discoveries into human and mouse systems.
∗ Corresponding author. Phone: 615 322 8547; Fax: 615 343 0704. E-mail address: [email protected] (D. Cortez). http://dx.doi.org/10.1016/j.dnarep.2015.11.001 1568-7864/© 2015 Published by Elsevier B.V.
Elledge discovered that the functional orthologues of the Rad53 kinase in mammalian cells were CHK1 and CHK2, defined mechanisms by which these kinases are activated by the upstream kinases ATR and ATM, and described how they signal to control cell cycle progression and other DDR responses [4–7]. He then turned his attention to how the damage sensing system works. Since ATR can be activated by many forms of DNA damage and by agents that stall DNA replication, the signal that ATR sensed needed to be something that all of these genotoxic stresses had in common. Elledge’s identification of a partner protein for ATR called ATRIP paved the way for his discovery that ATRIP serves as the sensor of single-stranded DNA through an interaction with the single-stranded DNA binding protein RPA [8,9]. As a post-doctoral fellow in the laboratory while these discoveries were being made, I can attest to the excitement and energy that made the lab such a fun place to work. No spare time was too short to fill with science. As Elledge went through the lab on the way out for the evening he would often say, “Walk with me” to discuss one last item on the way to the elevators. Two other postdocs, Yoli Sanchez and Jeff Bachant recall that Elledge often called the lab late in the evening to learn about new data or just talk ideas. Often he seemed to be speaking in a whisper as if he didn’t want to get caught by his family. As Bachant recalls, “Steve led the lab with something of a subdued ferocity. He pumped his ideas into it, and knew how to use the strengths of the group to get things done. He could bring people together and make things happen very quickly, and he also knew how to give people free reign to push into new areas.” Elledge set a high standard for his trainees and expected a high degree of independence. However, he cared about every project, and the resources and ideas were never limiting. He had a knack for identifying the key question or experiment, and he also found a way to make everyone in the lab productive. The lab atmosphere was a direct reflection of Elledge’s personality. His own words capture it best, “You are only as good as your next paper.” Elledge’s scientific contributions have since expanded to span many fields from ubiquitin-dependent proteolysis to cancer. A common theme is the development of new technologies and approaches. Elledge can be rightfully described as scientist and
D. Cortez et al. / DNA Repair 35 (2015) 156–157
engineer. He often seems most happy when he is devising new technologies or making them more useful. For many years the yeast two-hybrid strains and cDNA libraries he distributed freely were the best available empowering many investigators in many fields. He developed an early version of recombination-based cloning vectors and later developed methodologies and reagents for performing RNA interference screens in mammalian cells. Of course, Elledge’s work happened in the context of a rich and diverse research field with many investigators working to explain DDR mechanisms. There are too many people to acknowledge, but many key discoveries were made in other labs and the competition between labs spurred the rapid evolution of the field. We now know that there are hundreds of proteins that function in the DDR to maintain genome integrity. While the cataloguing of DDR proteins that Elledge started is likely nearing completion, the field will be busy for many decades deciphering DDR mechanisms, understanding the consequences for human disease when it doesn’t work, and understanding how we can intervene in these circumstances. Undoubtedly Elledge will continue to lead these endeavors in his own ongoing research, by creating new technologies to the benefit of everyone, and through his many trainees that have their own laboratories.
157
References [1] S.J. Elledge, R.W. Davis, Identification and isolation of the gene encoding the small subunit of ribonucleotide reductase from Saccharomyces cerevisiae: DNA damage-inducible gene required for mitotic viability, Mol. Cell. Biol. 7 (1987) 2783–2793. [2] Z. Zhou, S.J. Elledge, DUN1 encodes a protein kinase that controls the DNA damage response in yeast, Cell 75 (1993) 1119–1127. [3] J.B. Allen, Z. Zhou, W. Siede, E.C. Friedberg, S.J. Elledge, The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast, Genes Dev. 8 (1994) 2401–2415. [4] Y. Sanchez, C. Wong, R.S. Thoma, R. Richman, Z. Wu, H. Piwnica-Worms, S.J. Elledge, Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25, Science 277 (1997) 1497–1501. [5] S. Matsuoka, M. Huang, S.J. Elledge, Linkage of ATM to cell cycle regulation by the Chk2 protein kinase, Science 282 (1998) 1893–1897. [6] Q. Liu, S. Guntuku, X.S. Cui, S. Matsuoka, D. Cortez, K. Tamai, G. Luo, S. CarattiniRivera, F. DeMayo, A. Bradley, L.A. Donehower, S.J. Elledge, Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint, Genes Dev. 14 (2000) 1448–1459. [7] Y. Sanchez, J. Bachant, H. Wang, F. Hu, D. Liu, M. Tetzlaff, S.J. Elledge, Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms, Science 286 (1999) 1166–1171. [8] D. Cortez, S. Guntuku, J. Qin, S.J. Elledge, ATR and ATRIP: partners in checkpoint signaling, Science 294 (2001) 1713–1716. [9] L. Zou, S.J. Elledge, Sensing DNA damage through ATRIP recognition of RPAssDNA complexes, Science 300 (2003) 1542–1548.