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RNF4 interacts with both small ubiquitin‐like modifier and nucleosomes to promote the DNA damage response

Lynda M Groocock, Minghua Nie, John Prudden, Davide Moiani, Tao Wang, Anton Cheltsov, Robert P Rambo, Andrew S Arvai, Chiharu Hitomi, John A Tainer, Karolin Luger, J Jefferson P Perry, Eros Lazzerini‐Denchi, Michael N Boddy

Author Affiliations

  1. Lynda M Groocock1,
  2. Minghua Nie1,
  3. John Prudden1,
  4. Davide Moiani2,
  5. Tao Wang3,
  6. Anton Cheltsov4,
  7. Robert P Rambo5,
  8. Andrew S Arvai2,
  9. Chiharu Hitomi2,
  10. John A Tainer2,5,
  11. Karolin Luger3,
  12. J Jefferson P Perry*,2,6,
  13. Eros Lazzerini‐Denchi*,7 and
  14. Michael N Boddy*,1
  1. 1Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA
  2. 2Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
  3. 3Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute Colorado State University, Fort Collins, CO, USA
  4. 4Q‐MOL L.L.C., San Diego, CA, USA
  5. 5Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
  6. 6Amrita School of Biotechnology Amrita Vishwa Vidyapeetham Amritapuri, Kollam, Kerala, India
  7. 7Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
  1. * Corresponding author. Tel: +1 858 784 7042; Fax: +1 858 784 2265; E‐mail: nboddy{at}

    Corresponding author. Tel: +1 858 784 7659; Fax: +1 858 784 8926; E‐mail: edenchi{at}

    Corresponding author. Tel: +1 858 784 2284; Fax: +1 858 784 2277; E‐mail: jjperry{at}

View Abstract


The post‐translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin‐like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO‐modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome‐targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome‐targeting is crucially required for the repair of TRF2‐depleted dysfunctional telomeres by 53BP1‐mediated non‐homologous end joining.


Embedded Image

RNF4 is an important ubiquitin ligase in the DNA damage response (DDR) that targets SUMOylated proteins. This study shows that it also contains a nucleosome‐targeting motif that crucially supports the DDR genome‐wide.

  • RNF4 promotes ATM‐dependent 53BP1 recruitment and repair at dysfunctional telomeres.

  • RNF4 RING domain contains an RNF168 and RING1b‐related nucleosome‐targeting motif.

  • RNF4 recognizes both SUMO and nucleosomes to support DNA repair


  • Received December 13, 2013.
  • Revision received March 3, 2014.
  • Accepted March 4, 2014.
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