Every time a cell divides, it must accurately copy its DNA. With 3 billion “letters” in the human genome, this is no small task. My studies reveal the many steps and molecular actors involved, as well as how errors in DNA replication are involved in diseases that range from cancer to rare genetic disorders.
Bruce Stillman’s lab studies the process by which DNA is copied within cells before they divide in two. Working with yeast and human cells, Stillman and colleagues have identified many of the cellular proteins that function at the DNA replication fork during the S phase, the portion of the cell-division cycle when DNA synthesis occurs. Among these proteins are those that facilitate the assembly of chromatin, the protein–DNA complexes that form the chromosomes. Current research focuses on the mechanism that initiates the entire process of DNA replication in eukaryotic cells. At the heart of this mechanism is a protein that binds to “start” sites on the chromosomes, called the Origin Recognition Complex, ORC. The Stillman lab is part of an ongoing collaboration that determined the cryo-EM structure of ORC proteins in complex with a group of proteins, called a helicase, that unwind DNA during replication. These images offer molecular insights into how the helicase is loaded onto DNA. Stillman’s research also focuses on the process by which duplicated chromosomes are segregated during mitosis. They found ORC at centrosomes and centromeres, structures that orchestrate chromosome separation during mitosis. At centromeres, ORC subunits monitor the attachment of duplicated chromosomes to the mitotic spindle that pulls the chromosomes apart when they are correctly aligned. Stillman’s team has discovered that mutations in the Orc1 protein alter the ability of ORC to regulate both DNA replication and centrosome duplication. These mutations have been linked to Meier–Gorlin syndrome, a condition that results in people with extreme dwarfism and small brain size, but normal intelligence.
Elisabeth R. Woods Foundation donates to cancer research
July 17, 2018
On June 10th, Cold Spring Harbor Laboratory (CSHL) welcomed donors of the Elisabeth R. Woods Foundation to a special gathering in support of lung cancer research. Elisabeth Woods’ granddaughter, Mary Leonard, welcomed the distinguished guests, and in her opening remarks, told the story of her grandmother’s battle with non-small cell lung cancer and the Elisabeth...
Documentary film: THE MOST UNKNOWN
June 22, 2018
Cinema Arts Centre presents Science on Screen Sponsored by Stu & Ginger Polisner THE MOST UNKNOWN Tuesday, July 31 at 7:30 pm | Members $11 | Public $16 Includes reception and panel discussion with: Bruce Stillman, Ph.D., Cold Spring Harbor Laboratory Scott McLennan, Ph.D., Stony Brook University Lisa Miller, Ph.D., Brookhaven National Laboratory The Most Unknown is an ...
The case for open and inclusive science
June 8, 2018
Science has been one of the most important contributors to American national strength over the past century, but particularly since the Second World War. During that extraordinary crisis, outstanding national leaders recognized the untapped power of discoveries in a broad range of disciplines, from chemistry and physics to biology and engineering. In 1944, President Franklin...
Nation’s cancer centers endorse HPV vaccination
June 8, 2018
Cold Spring Harbor Laboratory joins NCI-designated cancer centers in endorsing the goal of eliminating HPV-related cancers Bruce Stillman, Ph.D., President and CEO of Cold Spring Harbor Laboratory, and David Tuveson, M.D., Ph.D., Director of CSHL’s NCI-designated Cancer Center, today joined with the leaders of other institutions nationwide in endorsing the following statement regarding revised recommendations...
Nature’s masterpiece: the brain
May 11, 2018
Since 1890, Cold Spring Harbor Laboratory (CSHL) has consistently advanced the frontiers of research and education in biology. How we have come so far is remarkable, considering that Darwin’s theory of evolution and Mendel’s explanation of genetics were at the cutting edge little more than a century ago. Curiosity-driven research, innovation and risk-taking underlie our...
Portrait of a Neuroscience Powerhouse
April 27, 2018
At noon every Tuesday from September through June, scenes from a revolution in neuroscience are playing out at Cold Spring Harbor Laboratory. Week after week, over 100 scientists cram themselves into a ground-floor meeting room in the Beckman Laboratory. It’s standing-room only as everyone in the Neuroscience Program settles in to hear details of the...
Cryo-EM imaging suggests how the double helix separates during replication
October 23, 2017
Cold Spring Harbor, NY — Life would be impossible if the DNA in dividing cells were replicated with anything less than near-perfect precision. Every time a nucleated cell commits to becoming two cells, every “letter” of its genome must be replicated once and only once. In humans, the task boggles the imagination. If unwound, the...
Protein complex that takes first steps in human DNA replication dance is captured at high atomic resolution
March 16, 2017
The Stillman and Joshua-Tor labs collaborated to obtain the structure of the active human Origin Recognition Complex (ORC), the proteins that control the initiation of DNA replication. Using both cyro-EM and x-ray crystallography, the labs obtained a high-resolution image of the ORC proteins bound to DNA, providing insights into the most fundamental process in cell proliferation.
CSHL joins NCI-designated cancer centers in endorsing updated HPV vaccination recommendations
January 11, 2017
Bruce Stillman, Ph.D., President and CEO of Cold Spring Harbor Laboratory, and David Tuveson, M.D., Ph.D., Director of CSHL’s NCI-designated Cancer Center, today joined with the leaders of other institutions nationwide in endorsing the following statement regarding revised recommendations concerning the HPV (human papillomavirus) vaccine: Recognizing low rates of human papillomavirus (HPV) vaccinations as a...
To divide or not: a cellular feedback loop that enables new cells to make a fateful decision
July 21, 2016
New research from the Stillman lab has revealed that key components of the DNA replication machinery participate in a feedback loop to control cell proliferation. The proteins—which are often mutated in cancer—provide a direct link between replication and proliferation.
Hossain, M. and Stillman, B. (2016) Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. Elife, 5
Sheu, Y. J. and Kinney, J. B. and Stillman, B. (2016) Concerted activities of Mcm4, Sld3 and Dbf4 in control of origin activation and DNA replication fork progression. Genome Res, 26(3) pp. 315-330.
Li, H. and Stillman, B. (2012) The origin recognition complex: a biochemical and structural view. In: The Eukaryotic Replisome: a Guide to Protein Structure and Function. MacNeill, Stuart (Ed.). Subcellular Biochemistry. Subcell Biochem, 62 pp. 37-58. Springer.
Mazurek, A. and Luo, W. and Krasnitz, A. and Hicks, J. and Powers, R. S. and Stillman, B. (2012) DDX5 regulates DNA replication and is required for cell proliferation in a subset of breast cancer cells. Cancer Discovery, 2(9) pp. 812-825.
Nakano, S. and Stillman, B. and Horvitz, H. R. (2011) Replication-coupled chromatin assembly generates a neuronal bilateral asymmetry in C. elegans. Cell, 147(7) pp. 1525-1536.Additional materials of the author at
CSHL Institutional Repository