Phosphatases and DNA double strand break repair

When cells suffer DNA damage – as little as a single break in one chromosome – they respond by activating the DNA damage checkpoint, which prevents cells from entering mitosis until there is enough time to to repair the damage.  The principal biochemical events in the checkpoint pathway are the phosphorylations of protein kinases by other protein kinases and eventually the phosphorylation of other proteins that regulate mitosis.    When repair is complete, the checkpoint must be turned off.  Not surprisingly, the enzymes that turn off the checkpoint are phosphatases that can remove the phosphates added by the protein kinases.

The Haber lab has previously shown that, in budding yeast, a pair of PP2C phosphatases known as Ptc2 and Ptc3 were important in turning off a key protein kinase, Rad53.  A member of another phosphatase subgroup, the PP4 phosphatase Pph3, dephosphorylates a target of the checkpoint kinases, histone protein H2A.  There is one aspect that they didn’t understand at all: It seems that the intensity of the checkpoint signals must grow the longer it takes to repair DNA damage, because deletions of ptc2 and ptc3 or a deletion of pph3 prevented cells from turning off the damage signal when it took a long time – 6 hours – to repair the damage, but they had much less effect on different repair events that could complete in 3-4 hours or in less than 2 hours.  So they decided to see what would happen if they created a yeast strain lacking all three phosphatases (ptc2 ptc3 pph3), leading to a paper appearing this month in the journal Molecular and Cell Biology.

To their surprise, these cells had a new defect: they couldn’t complete the repair event itself, rather than simply being defective in resuming mitosis after repair was completed.  The mutants could not properly initiate the small amounts of DNA copying that are required for repair.  Again, the severity of the defect depends on the length of the delay it takes to initiate the repair event itself.  The figure (right) shows that the triple mutant is also much more sensitive to DNA damaging agents such as the anti-cancer drug camptothecin (CPT) and to methylmethansulfonate (MMS). These data show a complex connection between DNA damage signaling and the repair process itself, and reveal new roles for the phosphatases in DNA repair.  The work was carried out primarily by graduate student Jung-Ae Kim, now a postdoc at Rockefeller University, with help by another grad student, Wade Hicks, and by an undergraduate Sue Yen Tay, and postdoc Jin Li. The work was supported by a research and a graduate student training grant from the NIH.

Dr. James Haber is to be named the 2011 Thomas Hunt Morgan medal recipient

Much like the scientist after whom this prestigious award is named,  Jim Haber has spent his scientific career asking big questions about genetics with the help of a small organism.  Instead of the humble fruit fly employed by Thomas Morgan, Jim and his students use the even humbler baker’s yeast Saccharomyces cerevisiae to study the complicated mechanisms of DNA recombination and repair.

Angie Brooksby (

Packed inside each little yeast cell is approximately 6000 genes worth of DNA, and the cell’s molecular machinery works very hard to fix any mistakes that might get incorporated into the genetic code.  Such mistakes can be caused by ultraviolet irradiation, mutagenic chemicals, and may even arise during the process of DNA replication itself.  Understanding how the yeast cell copes with these blows to its genetic integrity, as well as the consequences of mistakes gone unfixed, has been the focus of the Haber lab for over 20 years– but you don’t have to take my word for it.

In addition to recognizing purely scientific accomplishments, the Thomas Hunt Morgan medal is awarded to scientists who have proven to be excellent mentors to the students they work with.  In the spring of 2008, former students and post-docs of the Haber lab gathered at Brandeis to participate in a symposium honoring Jim’s 60th birthday, and the turn-out made clear that a sizeable amount of those who worked with Jim have either gone on to start successful labs of their own or entered into post-doctoral positions in labs of good repute.

When asked to reflect on what it’s been like to work with Jim, recent Haber lab graduate Dr. Wade Hicks answered that Jim “was a great mentor for me because he was always available to listen and talk about science.”  When further pressed against the journalistic blade and asked if Jim hosts any great parties, Wade coughed up that  “[Jim] does host the annual Halloween/pumpkin carving party that all the lab members’ kids enjoy…  What’s better than pumpkins, large knives, kids, and alcoholic beverages!?”

And finally, Jim’s eager willingness to talk about science extends beyond his lab and into the larger Life Sciences community– and likely beyond that.  Graduate students at departmental social events would be wise to chat Jim up regarding their projects– not to mention their gardens, favorite books, wine recommendations, etcetera.  In addition to being a great scientist, Jim is an all-around Good Guy.

Congratulations, Dr. Haber!

For further press see:

The Justice

Brandeis NOW

BIOL 99 AND NEUR 99 Senior Honors Talks

Senior honors presentations and defenses for Biology and Neuroscience are this week and next Monday.

Name      Faculty Sponsor & Committee  Time & Location of Talk

Biol 99

Alicia Bach Dagmar Ringe, Neil Simister, Liz Hedstrom May 10   3 pm    Bassine 251
Kristin Little Bruce Goode, Joan Press, Satoshi Yoshida May 6    10 am    Bassine 251
Spencer Rittner KC Hayes, Carolyn Cohen, Larry Wangh May 6    3 pm      Bassine 251
Danielle Saly Michael Rosbash, Mike Marr, Nelson Lau May 10   11 am   Bassine 251
Sue Yen Tay Jim Haber, Sue Lovett, Joan Press  May 7    11am     Bassine 251
Alan Tso Daniela Nicastro, Liz Hedstrom, Greg Petsko May 10   2 pm    Bassine 251
Hannah Worchel Jim Morris, Ruibao Ren, Paul Garrity   May 6    2 pm     Bassine 251

Neur 99
Sarah Pease Sue Paradis, Gina Turrigiano, Paul Miller  May 10   11 am   Volen 201
Solon Schur John Lisman, Eve Marder, Paul Miller May 6    10 am   Volen 201
Alexander Trott Leslie Griffith, Piali Sengupa, Melissa Kosinski-Collins May 6    11 am   Volen 201
Dylan Wolman Sue Paradis, Sacha Nelson, Piali Sengupta May 10   1 pm    Volen 201

Faculty research mentor (emphasized) is chair of the committee.

Haber elected to NAS

Brandeis Biology Professor Jim Haber has been elected to the National Academy of Sciences, according to a story at Brandeis NOW. For more about Prof. Haber and his laboratory’s research accomplishments, please see the Haber Lab website.

PhD Defense Season

It’s the season for PhD defenses…

  • Apr 20: Megan Zahniser (Biochemistry), On the structure of Benzaldehyde Dehydrogenase, a Class 3 Aldehyde Dehydrogenase from Pseudomonas putida – 2pm, Rosenstiel Penthouse
  • Apr 21: Chris Hoefler (Biochemistry/Bioorganic Chemistry). Inhibitors of IMPDH: Tools for Probing Mechanism and Function – 3:40 pm, Gerstenzang 122
  • Apr 22: Tepring Piquado (Neuroscience), Language and the aging brain – Thu 4/22/2010, 2 pm, Volen 201
  • Apr 23: Suvi Jain (Molecular and Cell Biology), Regulation of DNA Double-Strand Break Repair by the Recombination Execution Checkpoint in Saccharomyces cerevisiae – 3:30 pm, Rosenstiel 118
  • Apr 29: Ben Cuiffo (Molecular and Cell Biology), Targeting RAS palmitoylation in hematological malignancies – 2 pm, Abelson 131

Is my DNA fixed yet?

A broken chromosome (a double-strand DNA break) activates the DNA damage checkpoint to prevent cells from carrying out mitosis until the break has been repaired.  Repair of the break involves the modification and the removal of histone protein octamers from DNA around the break and these must be reestablished when repair is complete.  In a new paper in PNAS, Brandeis alumnus Jung-Ae Kim (Ph.D., Molecular and Cell Biology, 2008) and Professor James Haber show that when two of the major histone chaperone protein complexes (Asf1 and CAF-1) are deleted in yeast cells, their absence prevents cells from turning off the DNA damage checkpoint and hence cells stay permanently arrested.   These results suggest that cells specifically monitor the re-establishment of normal chromatin status after DNA repair.

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