PML nuclear bodies: dynamic sensors of DNA damage and cellular stress Graham Dellaire and David P. Bazett-Jones* Summary Promyelocytic leukaemia nuclear bodies (PML NBs) are generally present in all mammalian cells, and their integrity correlates with normal differentiation of pro- myelocytes. Mice that lack PML NBs have impaired immune function, exhibit chromosome instability and are sensitive to carcinogens. Although their direct role in nuclear activity is unclear, PML NBs are implicated in the regulation of transcription, apoptosis, tumour suppres- sion and the anti-viral response. An emerging view is that they represent sites where multi-subunit complexes form and where post-translational modification of regulatory factors, such as p53, occurs in response to cellular stress. Following DNA damage, several repair factors transit through PML NBs in a temporally regulated manner implicating these bodies in DNA repair. We propose that PML NBs are dynamic sensors of cellular stress, which rapidly disassemble following DNA damage into large supramolecular complexes, dispersing asso- ciated repair factors to sites of damage. The dramatically increased total surface area available would enhance interactions between PML-associated factors regulating DNA repair and apoptosis. BioEssays 26:963–977, 2004. ß 2004 Wiley Periodicals, Inc. Introduction Promyelocytic leukaemia nuclear bodies (PML NBs) are subnuclear protein structures, from 0.3 mm to 1.0 mm in diameter, that were originally characterized using human auto- antibodies from patients with primary biliary cirrhosis. (1–4) PML NBs are also referred to as PML oncogenic domains (PODS), Kremer (Kr) bodies and nuclear domain 10 (ND10). (1) Many cell types average 10 PML NBs per cell, hence the original designation as ND10; (3) though the actual number for a given cell type may range from 5–30 NBs and appears to be both cell-cycle and cell-type dependent. (5,6) PML NBs are often found juxtaposed to other nuclear structures such as splicing speckle domains, nuclear gems and Cajal bodies. Neither chromatin nor RNA is found within the central core of these bodies but newly synthesised RNA is associated with their periphery. (7) Although the major structural component of the PML NB is the PML protein, the nuclear antigen Sp100, a major auto- antigen in patients with primary biliary cirrhosis, was the first characterised protein to localise to this domain. (4) Later, the gene encoding the PML protein was isolated at the break point of a common (15,17) translocation found in patients suffering from acute promyelocytic leukaemia (APL), which results in the expression of an oncogenic fusion protein consisting of the PML protein fused to the retinoic acid receptor-a (RAR-a). (8–10) Nuclear domains containing PML are disrupted or dispersed in the lymphocytes of APL patients that express the PML-RAR fusion protein, which led to the alternate term PML oncogenic domains (PODs) to describe these bodies. (10) PML and Sp100 are founding members of a large family of proteins that contain a RING finger domain. The RING finger is BioEssays 26:963–977, ß 2004 Wiley Periodicals, Inc. BioEssays 26.9 963 Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada Funding agency: This work was supported by operating grants from the CIHR ; Grant numbers: MOP-64405, MOP-14311. *Correspondence to: David P. Bazett-Jones, Programme in Cell Biology, Research Institute, The Hospital for Sick Children,555 University Avenue, Toronto, ON, Canada M5G 1X8. E-mail: dbjones@sickkids.ca DOI 10.1002/bies.20089 Published online in Wiley InterScience (www.interscience.wiley.com). Abbreviations: ALT, alternative lengthening of telomeres; APL, acute promyelocytic leukaemia; ATM, Ataxia-telangiectasia-mutated gene product; ATR, ATM and Rad3-related protein; ATR; BLM; Bloom’s Syndrome gene product; BRCA-1, breast cancer-1; BS, Bloom’s Syndrome; CBP, CREB-binding protein; Chk2, checkpoint kinase 2; Daxx, death domain-associated protein 6; DSB, double-strand break; HAUSP, herpesvirus associated ubiquitin-specific protease; HIPK2, homeodomain interacting protein kinase-2; HSV-1, herpes simplex virus 1; IRIF, irradiation-induced foci; Isg20; interferon-stimulated gene product 20; NB, nuclear body; ND10; nuclear domain 10; NBS1, nibrin or Nijmegen breakage syndrome gene product; NER, nucleotide excision repair; PML, promyelocytic leukaemia gene product; POD, PML oncogenic domain; RBCC, RING-B-box-coiled-coil; SENP-1, sentrin-specific protease 1;SP100, nuclear antigen SP100; SUMO-1, small ubiquitin-like modifier 1; SuPr-1, SUMO-1 protease 1;TopBP1, DNA topoisomerase II binding protein; TP53INP1, tumour protein 53 inducible protein 1; TRF1 and 2, telomere repeat binding factor 1 and 2; UV, ultra-violet; WRN, Werner’s Syndrome gene product; WS, Werner’s Syndrome. Review articles