A team from David Pellman’s laboratory has defined a mechanism by which errors in mitosis lead to errors in whole chromosome segregation, result in massive chromosome damage when the missegregated chromosome is partitioned into a “micronucleus.”

Aneuploidy, abnormal numbers of whole chromosomes, is a signature feature of cancer, but its role in tumor development has been controversial, largely because of the paucity of mechanisms by which abnormal chromosome numbers might trigger tumor development. This contrasts with DNA breaks and chromosome rearrangements which cause cancer through mutations or expression changes in oncogenes or tumor suppressors. Micronuclei form around missegregated whole chromosomes or chromosome fragments, well described features of cancer cells. However, how these structures impact the cancer genome has been unclear. Pellman’s group developed methods to track the fate of newly formed micronuclei and found that they are defective in nuclear-cytoplasmic transport, and the recruitment of DNA replication licensing and repair factors. During S phase micronuclei undergo defective DNA replication that is not synchronized with DNA replication in the main nucleus. Upon the initiation of DNA replication, the chromosomes in the micronucleus are damaged. In many cases, these aberrantly replicated chromosomes shatter when cells enter mitosis, potentially because mitotic signals induce chromosome compaction. Imaging experiments established that chromosomes from micronuclei can be donated to daughter nuclei. Therefore, mutations acquired in micronuclei could be incorporated into the genome of a developing cancer cell. In addition to providing a mechanism by which errors in mitosis could lead to DNA damage, the findings provide a potential explanation for the recently discovered phenomenon of “chromothripsis.” Chromothripsis involves massive DNA damage restricted to a single chromosome or chromosome arm and is increasingly described as a feature of some cancer genomes. Karen Crasta, Neil Ganem and Regina Dagher from the Pellman lab all made major contributions to the study, which was also a collaboration with the laboratory of Dipanjan Chowdhury at DFCI [Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012, Jan 18]

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Howard Green, George Higginson Professor of Cell Biology selected as co-recipient of the 2012 March of Dimes Prize in Developmental Biology

The March of Dimes created the Prize as a tribute to Dr. Jonas Salk who developed the polio vaccine that bears his name. The March of Dimes Prize in Developmental Biology is awarded annually to investigators who have made a seminal discovery that has revealed a new principle of relevance to birth defects.  Dr. Green was chosen to receive the prize in recognition of his work on the genes involved in skin development and treatment of skin disorders.  The prize will be presented on the evening of 30 April 2012 at a black tie dinner and ceremony to be held in Boston.

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Dynein achieves processive motion using both stochastic and coordinated stepping

Inside each of our cells, tiny molecular motors are constantly working to shuttle materials needed to keep cells alive, allow cells to move and divide, and talk to their neighbors. These protein machines come in three models called “myosin,” “kinesin,” and “dynein.” All three models of motor are two-footed and use the energy from breaking chemical bonds to generate movement. The myosin and kinesin motors work by walking more or less like we do, one foot in front of the other in a straight line. The Reck-Peterson and Shih groups, at Harvard Medical School, have discovered that the third motor model, dynein, appears to be different, its two feet are at times uncoordinated and often veer from side to side (think drunken sailor). This mode of walking makes the dynein motor unique and may allow it to navigate obstacles while performing its transport functions in cells. Interestingly, their data also suggest that the dynein motor becomes more coordinated when it is hauling something large, implying that the motor can become more efficient when necessary. The dynein motor is critical for the function of every cell in our bodies, but defects in dynein-based transport have been linked to neurodegenerative (Lou Gehrig’s and Parkinson’s) and neurodevelopmental (lissencephaly) diseases. Deciphering the walking mechanism of this tiny machine may shed light on how it can malfunction in disease states. This work appeared online in Nature Structural and Molecular Biology on 8 January.

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