Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Dynamic XPD & Mre11-Rad50-Nbs1 DNA Repair Complexes: Disease-causing Mutations and Biological Outcomes

DNA ends at breaks, replication forks and telomeres are paradoxically often critically controlled for repair and integrity by a single trimeric complex of Mre11-Rad50-Nbs1 (MRN) dimers. MRN heterohexamer acts in key sensing, signaling, regulation, and effector responses to DNA double-strand breaks including ATM activation, homologous recombinational repair, microhomology-mediated end joining and, in some organisms, non-homologous end joining. Our results suggest that this is possible because each MRN subunit can exist in three or more distinct states; thus, the trimer of MRN dimers can exist in a stunningly large number of states. MRN can therefore act as a molecular machine that effectively assesses optimal responses and signals pathway choice based upon its states as set by cell status and the nature of the DNA damage. Diverse bulky lesions that distort double helical DNA are repaired by nucleotide excision repair (NER) orchestrated by the TFIIH complex enzymes: the XPB and XPD helicases and CAK kinase. Combined with mapping of XP patient mutations, detailed structural analyses provide a framework for integrating and unifying the rich biochemical and cellular information that has accumulated on NER over nearly forty years of study. This integration resolves puzzles regarding XP helicase functions and indicates that XP helicase positions and activities within TFIIH detect and verify damage, select damaged strand for incision, and coordinate repair with transcription and cell cycle through CAK signaling. Overall this concept that allosteric changes coordinate repair with replication, transcription, and cell cycle by coupling conformations to kinase activities provides opportunities to develop ligand master keys to cell biology and improved therapeutic interventions (1-4).


  1. R. S. Williams, G. Moncalian, J. S. Williams, Y. Yamada, O. Limbo, D. S. Shin, L. M. Groocock, D. Cahill, C. Hitomi, G. Guenther, D. Moiani, J. P. Carney, P. Russell, J. A. Tainer JA Cell 135, 97–109 (2008).
  2. L. Fan, J. O. Fuss, Q. J. Cheng, A. S. Arvai, M. Hammel, V. A. Roberts, P. K. Cooper, J. A. Tainer, Cell 133, 789-800 (2008).
  3. R. S. Williams, G. E. Dodson, O. Limbo, Y. Yamada, J. S. Williams, G. Guenther, S. Classen, J. N. M. Glover, H. Iwasaki, P. Russell, J. A. Tainer, Cell 139, 87-99 (2009).
  4. E. A. Rahal, L. A. Henricksen, Y. Li, R. S. Williams, J. A. Tainer, K. Dixon, Cell Cycle 9, 2866-2877 (2010).

John A. Tainer1, 2

1Lawrence Berkeley National Laboratory
Berkeley, CA; USA

2Department of Molecular Biology
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
La Jolla, CA 92037 USA

ph: 858-784-8438
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