New functions for chromatin remodelers

August 28, 2014

Large molecular motors consisting of up to a dozen different proteins regulate access to the genome, which is essential for the transcription of genes and for the repair of DNA damage. Susan Gasser and her team now reveal a new twist in the activity of such remodelers in the nucleus. In a recent paper in Molecular Cell they show that two related chromatin remodelers help transport broken DNA strands to specific sites in the nucleus for repair. Given the loss of genomic integrity that accompanies cancer and aging, it is not surprising to find that related remodelers are mutated early in the progression of human cancer.

The architecture of the genome is constantly changing. Depending on the developmental program of the cell, stretches of DNA are compacted and then released again, primarily by modulating the position and composition of histones, the abundant, positively charged proteins that organize DNA into . The dynamics of DNA accessibility is regulated by a large and diverse group of ATPases, the SWI/SNF family of chromatin remodelers, which shift, replace, and evict histones from chromatin.

Having previously shown a role for a specific chromatin remodeler, the INO80 complex, in the mobility of DNA in the nucleus, the Gasser laboratory has now gone further and explored the significance of DNA long-range movement in the nucleus. They found that the INO80 complex, together with a closely related remodeler called SWR-C (SRCAP in humans), is necessary for the shift of persistent double-strand breaks to sites of repair at the nuclear periphery. Two distinct anchorage sites favor distinct pathways of repair – one involves the processing of proteins bound at the site of damage whilst the other simply sequesters the break from a promiscuous invasion into other regions of the genome. Such invasion often leads to chromosomal translocations, which can generate cancer-promoting fusion proteins. The best-known example of this is a translocation generating the Bcr-Abl tyrosine kinase fusion that drives the development of chronic myelogenous leukemia (CML).

Double-strand break repair is a conserved mechanism that maintains genome integrity in all cells. Double-strand breaks occur during the replication of DNA when particularly difficult sequences (repeats) or RNA polymerases are encountered, or when cells are exposed to ionizing radiation. Unrepaired, such damage can lead to loss of genomic information and this in turn generates mutations or alleles that compromise control of cell division and/or cell fate. Aging and cancer both threaten patients with compromised DNA double-strand break repair machinery.

The results from the Gasser laboratory now shed light on an important contribution of chromatin remodelers to double-strand break repair. Two of the more common pathways of repair –end joining or the copying of genetic information from an attached sister chromatid – may not require the spatial reorganization of DNA breaks that the Gasser lab has observed. However, key backup mechanisms of break-induced replication or microhomology-mediated recombination seem to require this relocation event. "Up until now many have focused on chromatin remodelers in transcriptional regulation," comments Susan Gasser. "Yet our results point to important roles of these abundant molecular machines in DNA repair. Our work also underscores the importance of nuclear organization for specific repair pathways, something few have thought about at present."

Depending on the phase of the cell cycle, one or both of these chromatin remodelers (SWR-C or the INO80 complex) contributes to the transport of the persistent break, either to a nuclear pore or to a second conserved site on the inner nuclear membrane, where the conserved SUN-domain protein Mps3 suppresses random strand invasion. "Dissecting the different roles of chromatin remodelers and understanding their mode of function goes beyond mere academic interest," comments Gasser. "Many cancers become dependent on chromatin remodelers for survival of the replication damage that accompanies cellular transformation. A better understanding of the processes controlled by these remodelers may help us intervene to kill cancer cells selectively."

Explore further: On the move for repair

More information: Horigome C, Oma Y, Konishi T, Schmid R, Marcomini I, Hauer MH, Dion V, Harata M, Gasser SM (2014) "SWR1 and INO80 chromatin remodelers contribute to DNA double-strand break perinuclear anchorage site choice." Mol Cell. 2014 Jul 23. pii: S1097-2765(14)00536-X. DOI: 10.1016/j.molcel.2014.06.027

Related Stories

On the move for repair

April 17, 2012

Scientists from the Friedrich Miescher Institute for Biomedical Research have elucidated mechanisms that control DNA movement in the nucleus. They found that DNA with double-strand breaks moves more than undamaged DNA, thereby ...

How cells remodel after UV radiation

December 19, 2013

Researchers at the University of California, San Diego School of Medicine, with colleagues in The Netherlands and United Kingdom, have produced the first map detailing the network of genetic interactions underlying the cellular ...

Laser pulses reveal DNA repair mechanisms

August 9, 2013

A new straightforward method enables monitoring the response of nuclear proteins to DNA damage in time and space. The approach is based on nonlinear photoperturbation.

Histone exchanger comes into focus

September 16, 2013

The packaging of a gene has a major impact on its functional state and must be precisely controlled. A novel blend of methods has unveiled the architecture of a large protein complex that modulates DNA packing, and hints ...

Study finds crucial step in DNA repair

August 18, 2014

Scientists at Washington State University have identified a crucial step in DNA repair that could lead to targeted gene therapy for hereditary diseases such as "children of the moon" and a common form of colon cancer.

Recommended for you

Energy-saving LEDs boost light pollution worldwide

November 22, 2017

They were supposed to bring about an energy revolution—but the popularity of LED lights is driving an increase in light pollution worldwide, with dire consequences for human and animal health, researchers said Wednesday.

Re-cloning of first cloned dog deemed successful thus far

November 22, 2017

(—A team of researchers with Seoul National University, Michigan State University and the University of Illinois at Urbana-Champaign has re-cloned the first dog to be cloned. In their paper published in the journal ...

Testing the advantage of being left-handed in sports

November 22, 2017

(—Sports scientist Florian Loffing with the Institute of Sport Science, University of Oldenburg in Germany has conducted a study regarding the possibility of left-handed athletes having an advantage over their ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.