It is well established that chromosome instability is an underlying cause of several age-related disorders, including cancer and neurodegenerative diseases. Changes in chromosome number and structure can be triggered not only by DNA damaging agents, but also by intrinsically unstable regions of the human genome itself – which we term the ‘enemies within’. The overarching goal of the Center for Chromosome Stability (CCS) is to functionally annotate these ‘enemies within’, and determine how they drive tissue aging and limit cell immortality.

The CCS currently comprises 7 core research groups. In addition, there are two affiliated groups headed by Andres Lopez-Contreras and Andrew Blackford. Andres was a PI in the CCS until 2020, but now runs a group at CABIMER in Seville, Spain. Andrew was recruited in 2023 from the University of Oxford. The different research groups possess complementary expertise in genetics, biochemistry, structural biology and molecular/cell biology. The leaders of the research groups are listed below, with a short description of research interest and a link to the home page of the group.




Our research is multidisciplinary and collaborative, and centers on computational studies of functional, structural, comparative genomics and transcriptomics. We do this to understand
1) the epigenomic changes just before and after mammalian fertilization as well as the effects on embryo fitness, and
2) DNA template conflicts e.g. the replication stress occurring in the first cell division of mammalian embryos.

At conception, we all inherit a fortune. Six billion base-pairs worth of instructions for how to produce each and every specific component and emerging properties of our cells, body-plan, physiology, mind, and more.

These legacy instructions are the software needed to program the matter we consist of, and they are literally ancient. However, while much of our programming was optimized already a billion years ago, other components has only recently been introduced into our genomes.

The quest to adapt to changing environments and conquer ecological niches demands that all organisms include a certain level of creative destruction, so that fitting changes are inherited in the offspring through trial-and-error.

As with any large and comprehensive set of instructions, our genome therefore contains conflicting, ambiguous, repurposed, obsolete, inflated, suboptimal, and even selfish components.

Every genome therefore has to contain and uphold a range of conflicts of interests and trade-offs, and much of the collective action of DNA-bound factors and epigenetic modifications conceivably serve to ensure a coordinated and appropriate use of the genome.

Our overarching passion is to seek understanding of how inbuilt genomic conflicts of interests are handled by mammalian organisms.

A key interest is to understand the remarkable environment existing when the mammalian oocyte is fertilized and become an embryo. During this process, extensive genomic reprogramming happens, epigenetic marks are rewritten on a global scale, and retrotransposons are allowed to be strikingly active and roam more freely than at any other stage of mammalian life – all factors that can threaten the integrity of the genome (Bhowmick, Lerdrup, Mol Cell, 2022; Sankar, Lerdrup, Manaf et al, Nat Cell Biol, 2020; Dahl et al, Nature, 2016, Manaf, Lerdrup et al, submitted).

Our work has also led to development of a comprehensive software suite for data analysis to increase productivity and deeper understanding of genome-wide data (Lerdrup et al, Nat Struct Mol Biol, 2016,

Homepage for Lerdrup Group

Our group aims to understand the processes cells use to counteract replication stress caused by either internal factors or external factors, and why some regions in the genome are particularly susceptible to those factors.

1) The analysis of mechanisms underlying MiDAS

It is well established that incomplete replication can cause a delay in chromatin condensation that leads to the ‘expression’ of common fragile sites (CFSs) [1, 2]. CFSs are hot spots for deletions and chromosome rearrangements in cancer [3]. We previously have taken part in the discovery of a process called mitotic DNA synthesis (MiDAS) that operates in mitosis is a strategy used by human cells to rescue the incomplete replication at those loci, particularly in cancers cells that has elevated replication stress (RS) [4-7] (Figure 1). Particularly, both RAD52 and POLD3 play a crucial role in MiDAS. Our recent findings demonstrate that: i) RTEL1, a DNA helicase, can prevent the accumulation of G-quadruplex-associated R-loops at difficult-to-replicate loci including CFSs in the human genome in S phase, and can facilitate MiDAS in M phase [8]; ii) both translesion polymerases and replication replication polymerase delta play a crucial role in completing MiDAS [9]. In addition, using a BioID strategy [10], we have identified a panel of factors that could potentially work closely with POLD3 when cells are challenged with RS. We are now investigating the functions of these factors and their relevance to MiDAS.

figure 1
Figure 1: An image of mitotic DNA synthesis (MiDAS) detected in a cancer cell derived from a human female patient with bone cancer. A normal cell has 46 chromosomes while this cell has 78 chromosomes. MiDAS is shown in red, and chromosomes are in blue with their ends being marked in green.

2) The analysis of folate deficiency induced genome instability

Folate deficiency is known to be associated with a diverse range of human disorders including fetal neural tube defects, age-associated dementia, infertility, and some type of cancers. Intriguingly, folate deficiency is known to cause the expression of group of rare fragile sites, all of which contain long stretch of CGG simple repeats.  The most well studied locus of this kind is called FRAXA that is associated with Fragile X syndrome (FXS). Using FXS cells as a model, we demonstrated that folate deprivation triggers the extensive missegregation and aneuploidy of chromosome X [11], and MiDAS at the FRAXA locus via the break-induced DNA replication (BIR) that requires the SLX1/SLX4 endonuclease complex, the RAD51 recombinase and POLD3 [12]. Recently, based on a combination of bioinformatic and cellular biology analysis, we demonstrated that folate deficiency could cause the abnormal segregation of a region with CG-Rich trinucleotide repeats on human chromosome 2 [13]. We are currently investigating other regions that are vulnerable to folate deficiency in the human genome, and the strategies cells employ to maintain the stability of those regions (Figure 2).

figure 2

Figure 2. MiDAS occurs at FRAXA in response to folate stress. GM09237 cells, which have over 900 CGG repeats at FRAXA, were treated with fluorodeoxyuridine (FdU) for 17 hours, subjected to EdU incorporation in M phase, and then harvested for metaphase chromosome analysis. The location of FRAXA was validated by a FISH probe. Representative images of FRAXA loci (green) and an EdU locus (magenta) are shown. Yellow arrow indicates a fragile FRAXA locus. Unt, untreated. FdU, cells treated with FdU.

Homepage for Liu Group
(Department of Cellular and Molecular Medicine)


"The molecular mechanisms of faithful genome replication"

Our lab aims to understand the molecular mechanisms that maintain eukaryotic genome stability during DNA replication using a combination of genetic, biochemical, cellular, and structural techniques, including cryo-EM.

Accurate chromosome replication is essential for controlled cell proliferation and the faithful transfer of genetic information from one generation to the next. A failure to maintain genome stability can cause diverse developmental disorders and age-related diseases, including accelerated neurodegeneration and cancer. Eukaryotic genomes are duplicated by large, multi-component protein machines called replisomes. At their core, replisomes consist of a helicase that unwinds duplex DNA and polymerases that catalyse the synthesis of new DNA molecules according to the parental template. A diverse range of accessory factors are also required facilitate the faithful replication of eukaryotic chromosomes, which contain an array of ‘obstacles’ that could otherwise stall or inhibit the replication machinery. Together, the replisome and accessory factors regulate the timing, speed and accuracy of replication, minimising replication errors and preventing genome instability. Our group aims to understand the molecular mechanisms by which eukaryotic replisomes and accessory factors preserve genome stability during DNA replication and how failures in these mechanisms cause disease. Ultimately, we plan to use the knowledge we gain to develop novel therapeutic approaches to prevent or treat human disorders linked to genome instability.

figure -potential obstacles to dna replication
The replisome is a complex multi-component molecular machine that must overcome diverse ‘obstacles’ to faithfully replicate eukaryotic chromosomes. Our group uses a range of genetic, biochemical, cellular and structural techniques (including cryo-EM), to investigate the molecular mechanisms underlying replisome assembly and function.

Homepage for Miller Group
(Department of Cellular and Molecular Medicine)



Affiliated Research Group




Mutations caused by DNA damage enable a normal cell to become cancerous. This is highlighted by the fact that individuals with mutations in many genes involved in DNA damage recognition, signalling and repair are predisposed to cancer, and that somatically acquired defects in such genes can drive tumour formation. Furthermore, some of the most effective cancer treatments work in tumour cells by inducing DNA damage, particularly DNA double-strand breaks, which are especially toxic and difficult to repair accurately without introducing mutations. Exploiting knowledge of DNA double-strand break repair is therefore likely to lead to more effective and personalised cancer therapies and treatments for patients with DNA repair disorders in future.

The aim of our research is to gain a greater understanding of the signalling mechanisms cells use to coordinate DNA double-strand break recognition and repair with cell cycle checkpoint activation and apoptosis. To achieve this, we are using cutting-edge bioinformatics, proteomics, microscopy and CRISPR-Cas9 gene-editing techniques to answer specific questions related to DNA damage signalling. In doing so, we hope to provide novel insights into carcinogenesis and how it is held at bay by the cell’s DNA damage response system. We also aim to translate our research to develop novel potential cancer treatments. In particular, we are interested in the potential utility of signalling events for use as biomarkers and to identify novel targets in the DNA damage response for anti-cancer drugs.

Homepage for Blackford Group
(Department of Cellular and Molecular Medicine)