Matt Michael

• Damon Runyon Fellow, U.C. San Diego, 1996 – 2000

Summary Statement of Research Interests

Matt Michael’s lab studies genome biology and is focused on two separate problems. One, how is gene expression controlled globally, at the level of the entire genome? And two, what are the biochemical mechanisms in play that promote the maintenance of genome stability?

The Michael Lab has recently discovered a novel molecular pathway that silences gene expression globally during germline development in C. elegans. We found that when embryos hatch into L1 larvae in an environment lacking nutrients then the energy sensing kinase AMPK is activated in their primordial germ cells (PGCs). AMPK then promotes a global chromatin compaction (GCC) event, one that requires topoisomerase II, condensin II, and components of the H3K9me pathway used to build heterochromatin. GCC then reorganizes the genome in a manner that silences all gene expression. In more recent work we discovered that the same GCC event is required for genome silencing in oocytes and spermatocytes as they enter meiotic prophase. Remarkably, in L1s that have been given food, the PGC genome is reactivated in a manner requiring the deposition of numerous DNA double-strand breaks (DSBs) throughout the germline genome. Current projects in the lab include studying how GCC occurs mechanistically and how the system is under signal-mediated control. We are also studying how the DSBs are produced and what their role is in genome activation.

The Michael Lab has also had a long-standing interesting in how DNA-based signal transduction pathways prevent genome destabilization. Our current focus is on how the ATR kinase is activated by DSBs. ATR is crucial for allowing cells to survive genotoxic threats and forms an important barrier to tumorigenesis. ATR activation by DSBs allows the cell to delay cell cycle progression while the DSB is being repaired, and ATR signaling is also important for repair of the DSB, in a poor defined manner. We use Xenopus egg extracts to study ATR, and we are interested in how ATR signaling interfaces with the two DSB end-joining repair pathways, NHEJ and MMEJ (or alt-EJ). Very little is known about how ATR signaling interfaces with end-joining mediated repair and the Xenopus egg extract system is an ideal tool to make headway into this important problem.

Research Keywords

cell cycle regulation, biochemical mechanisms for cell cycle checkpoints, cell cycle control during early embryonic development, germline specification, DNA breaks during gene activation

Journal Article

• Ruis, K., Huynh, O., Montales, K., Barr, N. A., Michael,Ruis, W. M., Huynh, O., Montales, K., Barr, N. A., Michael,Ruis, W. M., Huynh, O., Montales, K., Barr, N. A., Michael, W. M. (2022). Delineation of a minimal topoisomerase II binding protein 1 for regulated activation of ATR at DNA double-strand breaks. The Journal of biological chemistry. Vol. 298 (7), pp. 101992. PubMed Web Address
• Montales, K., Ruis, K., Lindsay, H., Michael,Montales, W. M., Ruis, K., Lindsay, H., Michael,Montales, W. M., Ruis, K., Lindsay, H., Michael, W. M. (2022). MRN-dependent and independent pathways for recruitment of TOPBP1 to DNA double-strand breaks. PloS one. Vol. 17 (8), pp. e0271905. PubMed Web Address
• Belew, M. D., Chien, E., Wong, M., Michael,Belew, W. M., Chien, E., Wong, M., Michael,Belew, W. M., Chien, E., Wong, M., Michael, W. M. (2021). A global chromatin compaction pathway that represses germline gene expression during starvation. The Journal of cell biology. Vol. 220 (9) PubMed Web Address
• Montales, K., Kim, A., Ruis, K., Michael,Montales, W. M., Kim, A., Ruis, K., Michael,Montales, W. M., Kim, A., Ruis, K., Michael, W. M. (2021). Structure-function analysis of TOPBP1’s role in ATR signaling using the DSB-mediated ATR activation in Xenopus egg extracts (DMAX) system. Scientific reports. Vol. 11 (1), pp. 467. PubMed Web Address
• Kim, A., Montales, K., Ruis, K., Senebandith, H., Gasparyan, H., Cowan, Q., Michael,Kim, W. M., Montales, K., Ruis, K., Senebandith, H., Gasparyan, H., Cowan, Q., Michael,Kim, W. M., Montales, K., Ruis, K., Senebandith, H., Gasparyan, H., Cowan, Q., Michael, W. M. (2020). Biochemical analysis of TOPBP1 oligomerization. DNA repair. Vol. 96, pp. 102973. PubMed Web Address
• Wong, M. M., Belew, M. D., Kwieraga, A., Nhan, J. D., Michael, W. M. (2018). Programmed DNA Breaks Activate the Germline Genome in Caenorhabditis elegans. Developmental Cell. Vol. 46, pp. 302-315. PubMed Web Address
• Gasparyan, H. J., Kroh, J., Michael, W. M., Petreaca,Gasparyan, R. C., Kroh, J., Michael, W. M., Petreaca,Gasparyan, R. C., Kroh, J., Michael, W. M., Petreaca, R. C. (2018). Development of the SapI/AarI Incision Mediated Plasmid Editing Method. Journal of molecular biology. Vol. 430 (10), pp. 1426-1430. PubMed Web Address
• Michael,Michael,Michael, W. M. (2017). Asymmetric distribution of cyb-3 in 4-cell stage embryos. microPublication biology. Vol. 2017 PubMed Web Address
• Michael, W. M. (2016). Cyclin CYB-3 controls both S-phase and mitosis and is asymmetrically distributed in the early C. elegans embryo. Development. Vol. 143 (17), pp. 3119-3127. PubMed Web Address
• Acevedo, J., Yan, S., Michael, W. M. (2016). Direct Binding to Replication Protein A (RPA)-coated Single-stranded DNA Allows Recruitment of the ATR Activator TopBP1 to Sites of DNA Damage. The Journal of Biological Chemistry. Vol. 291 (25), pp. 13124-31. PubMed Web Address
• Stevens, H., Williams, A. B., Michael, W. M. (2016). Cell-Type Specific Responses to DNA Replication Stress in Early C. elegans Embryos. PloS one. Vol. 11 (10), pp. e0164601. PubMed Web Address
• Butuci, M., Williams, A. B., Wong, M. M., Kramer, B., Michael, W. M. (2015). Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells. Developmental Cell. Vol. 34 (1), pp. 85-95. PubMed Web Address
• Butuci, M., Wong, M. M., Michael, W. M. (2015). Trouble in Transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability. Worm. Vol. 4 (4), pp. e1115946. PubMed Web Address
• Bai, L., Michael, W. M., Yan, S. (2014). Importin ß-dependent nuclear import of TopBP1 in ATR-Chk1 checkpoint in Xenopus egg extracts. Cellular Signalling. Vol. 26 (5), pp. 857-67. PubMed Web Address
• Murphy, C. M., Michael, W. M. (2013). Control of DNA replication by the nucleus/cytoplasm ratio in Xenopus. The Journal of Biological Chemistry. Vol. 288 (41), pp. 29382-93. PubMed Web Address
• Van, C., Yan, S., Michael, W. M., Waga, S., Cimprich, K. (2010). Continued primer synthesis at stalled replication forks contributes to checkpoint activation. The Journal of Cell Biology. Vol. 189 (2), pp. 233-46. PubMed Web Address
• Williams, A. B., Michael, W. M. (2010). Eviction notice: new insights into Rad51 removal from DNA during homologous recombination. Molecular Cell. Vol. 37 (2), pp. 157-8. PubMed Web Address
• Yan, S., Michael, W. M. (2009). TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation. Cell Cycle. Vol. 8 (18), pp. 2877-84. PubMed Web Address
• Yan, S., Michael, W. M. (2009). TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks. The Journal of Cell Biology. Vol. 184 (6), pp. 793-804. PubMed Web Address
• Kim, S. H., Michael, W. M. (2008). Regulated proteolysis of DNA polymerase eta during the DNA-damage response in C. elegans. Molecular Cell. Vol. 32 (6), pp. 757-66. PubMed Web Address

• American Cancer Society Research Scholar, 2003 – 2006
• NSF CAREER Award, 2002 – 2005
• Searle Scholar, 2001 – 2004
• Damon Runyon Postdoctoral Fellow, 1997 – 2000