Workshop Title: DNA REPAIR DEFICIENT SYNDROMES: MOLECULAR AND CLINICAL
ABNORMALITIES

**Background**

This meeting is a follow up of the one we held May 23-26, 2004, at the
National Conference Center, Virginia, USA, supported by the ORD, NIH. A
report of that meeting was published (Bohr et al., 2005)

That meeting brought together a group of clinicians and basic scientists
working on rare DNA repair deficient syndromes. It was quite successful
at bringing these different perspectives together. In addition, for the
first time these researchers met with representatives of organizations
of families that have children affected by these disorders. Further, we
were able to present a patient and his mother to the collected
scientists/physicians. For many of the basic researchers this was the
first time that they had ever seen a patient despite spending their
entire careers working on molecular mechanisms of these diseases.

We received extensive positive comments from the participants after the
meeting and Dr. Stephen Groft from ORD was present for a panel
discussion. All urged us to hold a follow up meeting of the same type,
again bringing together the basic and clinical scientists along with
patient representatives.

The devastating autosomal recessive genetic disorder Cockayne syndrome
(CS) arises from mutations in the CSA and CSB genes. CS is characterized
by progressive multisystem degeneration and is classified as a segmental
premature aging syndrome. The CSB protein is at the interface of
transcription and DNA repair, being involved in transcription-coupled
and global genome DNA repair as well as in general transcription. Recent
structure-function studies indicate a process dependent variation in the
molecular mechanism employed by CSB and provide starting grounds for a
description of the mechanisms and their interplay.

CS patients are characterized by traits reminiscent of normal aging such
as systemic growth failure, progressive neurological degeneration and
cataracts, and CS has thus been classified as a segmental premature
aging syndrome. The majority of CS cases are caused by defects in the
Cockayne syndrome complementation group B protein. CS can be described
as a transcription and DNA repair deficiency syndrome without increased
cancer frequency.

Xeroderma pigmentosum (XP) is a related autosomal recessive disorder of
DNA repair. These patients are sun sensitive and have a 1000 fold
increased risk of developing cancer in sun exposed sites (such as skin,
eyes and tip of tongue). There is a 50 year reduction in age of onset of
cancer in XP patients. In addition to skin abnormalities some XP
patients suffer from a progressive neurological degeneration. XP
patients have defects in nucleotide excision repair (NER) (XP
complementation groups A-G) or in an error prone DNA polymerase (pol
eta).

Trichothiodystrophy (TTD) is a third autosomal recessive disorder of DNA
repair. These sun sensitive patients have sulfur deficient brittle hair,
short stature and developmental delay, without an increased risk of skin
cancer. Surprisingly, these patients have defects in some of the same
NER genes as XP patients. These genes (XPB and XPD) are helicases that
are involved both in NER and as part of the basal transcription factor
TFIIH. Like CS,TTD may be a transcription DNA repair deficiency.

Cellular DNA is exposed to various endogenous and exogenous damaging
agents. The inflicted lesions are normally repaired by the different
pathways of DNA repair. However, not all lesions may be removed and a
gradual accumulation of DNA lesions during the life of the cell and the
whole organism has been suggested to contribute to the normal aging
process. Among the major DNA repair pathways are NER and base excision
repair (BER), each responsible for excising and repairing different
lesions in DNA. NER is effective upon bulky adducts and intrastrand
cross links, while BER recognizes single-strand breaks and minor base
lesions such as oxidative modifications and methylations.

NER can be divided in global genome repair (GGR) and transcription
coupled repair (TCR) depending upon the primary damage recognition step.
TCR is the preferential repair of the transcribed strand of active
genes, where lesion induced stalling of the transcribing RNA polymerase
serves as a signal for recruitment of factors responsible for NER. GGR
is, as implied by the name, the repair of lesions situated in all
regions of the genome, and the lesion recognition is mediated by an as
yet unknown combination of the factors. In BER, damaged bases are
recognized by various DNA glycosylases, each with specific, yet
overlapping lesion targets. The DNA glycosylase is responsible for
removing its cognate aberrant base by hydrolysis of the N-glycosylic
bond. This step is succeeded by cleavage of the DNA backbone and removal
of the remaining deoxyribose moiety by an endonuclease activity, either
pertaining to the DNA glycosylase or to APE1. Finally, a resynthesis
step of one to seven bases depending on the subpathway employed restores
the integrity of DNA.

The CSB protein seems to be involved in several different processes
including transcription by RNA polymerase I, II and possibly III,
transcription coupled NER and BER of some types of oxidative damage in
nuclei and mitochondria. Similarly, NER proteins XPB, XPD and TTD-A are
involved in transcription and repair. The many roles of CSB and NER
proteins provide an explanation for the varied multisystem
manifestations of the CS, XP and TTD phenotypes and provide rich grounds
for the influence of genetic background.

## 

## Purpose of meeting

The purpose of this workshop is to gather leading scientists and
clinicians in this very active area of research. The clinical and
mechanistic aspects of CS and related DNA repair/transcription defective
disorders such as the XP and TTD will be explored. Our goal is to
develop new multidisciplinary collaborations, interactions and
relationships that can lead to a greater understanding of the
patho­physiological mechanisms involved in these disorders and to
conceive new therapeutic strategies for their treatment.

**Format**

Short presentation followed by discussion. General discussion sessions.

**Plans for publicizing meeting and dissemination of meeting outcome**

We plan to publish a meeting report similar to the last one

**Plans to assess the meeting's effectiveness in terms of goals, use of
results, or development of specific research initiatives**

A questionnaire will be distributed

**Proposed participants**

Basic Researchers:

1\. Vilhelm A. Bohr, NIA, NIH. 2. Kenneth H. Kraemer, NCI, NIH. 3. Jan
H. Hoeijmakers, Rotterdam University, The Netherlands. 4. Leon
Mullenders, Leiden Univ., The Netherlands. 5. Kyoiji Tanaka, Osaka
University, Japan. 6. Ole Petter Ottosen, Univ of Norway. 7. Tone
Tonjum, Univ. of Oslo 8. Arne Klungkand, Oslo University, Norway. 9.
Berndt Epe, Univ. of Mainz, Germany. 10. Jonathan Eisen, Celera Corp,
Rockville, MD. 11. Alain Sarasin, Paris Univ, France. 12. David Levens,
NCI, NIH. 13. Jean Marc Egly, Univ. Strasbourg, France. 14.Yves Pommier,
NCI, NIH. 15. Alan Lehmann, Sussex Univ, UK 16. P.J. Brooks NIAAA, NIH,
17. Miria Stefanini, Pavia, Italy. 18. Wim Vermeuhlen, Erasmus Univ.,
Rotterdam. 19. Tinna Stevsner, Aarhus Univ., Denmark. 20 Koos Jaspers,
Erasmus Univ, Rotterdam. 21. James Cleaver UCSF 22. Phil Hanawalt,
Stanford, CA. 23. Doug Brash, Yale

Clinical Researchers:

1\. John DiGiovanna, NCI, NIH. 2 Raffi Schiffman NINDS, NIH 3. Isabel
Rapin, NY, NY. 4. Mark Pittlekow, Mayo Clinic, Rochester, MN 5. Vera
Price, UCSF

6\. Hanoch Slor, Tel Aviv, Israel 7. Roger Brumback, Creighton Univ 8.
Maria Hordinsky, Univ of Minnesota 9. W.Clark Lambert, NJ College of
Medicine 10. Martha Nance, Univ of Minnesota 11. Edward Neilan, Boston
Children's Hospital

Patient Representatives:

We will contact the CS Society, the XP Society and the Foundation for
Ichthyosis and Related Skin Diseases to send representatives to the
meeting.