Review Chromatin and cell death Marco E. Bianchi * , Angelo Manfredi San Raffaele Scientific Institute, via Olgettina 58, 4 Piano A1, Milan I-20132, Italy Received 23 September 2003; received in revised form 8 October 2003; accepted 9 October 2003 Abstract HMGB1, a very mobile chromatin protein, leaks out from necrotic cells and signals to neighbouring cells that tissue damage has occurred. At least one receptor for extracellular HMGB1 exists, and signals to different cells to divide, migrate, activate inflammation or start an immune response. Remarkably, apoptotic chromatin binds HMGB1 irreversibly, thereby ensuring that it will not diffuse away to activate responses from neighbouring cells. Thus, dying cells use their own chromatin to signal how they have died. We argue that the nuclear events in apoptosis serve to control the molecular signals that dying cells send out. D 2004 Elsevier B.V. All rights reserved. Keywords: Chromatin; Histone; HMGB; Apoptosis; Necrosis 1. Introduction Cells must be able to respond to a variety of cues from their environment. Among these, information about the well-being of other cells in the same tissue, and in some cases in distant areas of the body, is of critical importance. Cells undergo unprogrammed death or necrosis mainly as a consequence of mechanical trauma, severe hypoxia, some types of infection, or poisoning. Cells can also undergo programmed death or apoptosis: in these cases, cells put an end to their existence because they have either suffered irreparable damage, are infected, do not receive appropriate signals from their environment, or are specifically told to die by nearby cells. Apoptosis is generally the result of a decision of the cell involved, and cells that have died this way often only need to send out an ‘‘eat me’’ signal to macrophages and other professional or amateur phagocytic cells. Necrosis, on the other hand, is the consequence of an unpredictable or uncontrolled event; it has to be communi- cated to the surrounding cells and the signal must be amplified to elicit cellular responses to control and repair the damage. Surprisingly, it turns out that the signal broadcast by necrotic cells is their own chromatin. We will review here the evidence that led to the identification of chromatin protein HMGB1 (High Mobility Group B1) as the necrosis signal, and some of the ways cells use this signal. Finally, we will argue that the nuclear events of apoptosis (histone modification and chromatin condensation) have evolved to control the signalling from the dying cell to its neighbours. 2. HMGB1’s role in the nucleus HMGB1 (formerly named HMG1 but also known as amphoterin and sulfoglucuronyl carbohydrate binding pro- tein, SBP-1) was identified almost 30 years ago; the name simply indicates that it is a small protein (215 residues) that runs fast in SDS-polyacrylamide gels [1]. Structurally, it has two consecutive L-shaped domains (called HMG boxes) and a 30-amino-acid-long acidic ‘‘tail’’, connected by short peptides [2]. HMGB1 binds to DNA without sequence specificity. Yet the protein facilitates numerous nuclear transactions, includ- ing transcription, replication, V(D)J recombination, and DNA transposition, and interacts with p53, steroid hormone receptors, NF-nB, homeobox-containing proteins and TBP [3,4]. HMG boxes bind to the minor groove of B-type DNA, and upon binding they distort the double helix sharply, inducing bends of 90j and more. The architectural changes induced in DNA are believed to facilitate the assembly of multiprotein complexes at the distorted site. HMGB1 also binds with relatively high affinity to already distorted DNA, such as four-way junctions, 0167-4781/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbaexp.2003.10.017 * Corresponding author. Tel.: +39-0226434774; fax: +39-0226434861. E-mail address: bianchi.marco@hsr.it (M.E. Bianchi). www.bba-direct.com Biochimica et Biophysica Acta 1677 (2004) 181 – 186