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FANCM As an Anti-Cancer Target in Alternative Lengthening of Telomeres

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FANCM As an Anti-Cancer Target in Alternative Lengthening of Telomeres NUCLEUS 2019, VOL. 10, NO. 1, 221–230 https://doi.org/10.1080/19491034.2019.1685246 COMMENTARY ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres Julienne J O’Rourke a,b#, Rohan Bythell-Douglas a, Elyse A Dunn a, and Andrew J Deans a,b aGenome Stability Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Australia; bDepartment of Medicine, (St Vincent’s) University of Melbourne, Fitzroy, Australia ABSTRACT ARTICLE HISTORY Break-induced replication is a specific type of DNA repair that has a co-opted role in telomere Received 2 August 2019 extension by telomerase-negative cancer cells. This Alternative Lengthening of Telomeres (or Revised 17 October 2019 ‘ALT’) is required for viability in approximately 10% of all carcinomas, but up to 50% of the soft- Accepted 21 October 2019 tissue derived sarcomas. In several recent studies, we and others demonstrate that expression and KEYWORDS activity of FANCM, a DNA translocase protein, is essential for the viability of ALT-associated Telomeres; DNA repair; cancers. Here we provide a summary of how and why FANCM depletion leads to deletion of ALT- Fanconi anemia; controlled cancers, predominantly through a hyper-activation of break-induced replication. We chemotherapy; break- also discuss how FANCM can and has been targeted in cancer cell killing, including potential induced replication; opportunities in ALT and other genetic backgrounds. precision medicine; synthetic lethal Mechanism of Alternative Lengthening of Cancers utilizing ALT have several unique charac- Telomeres (ALT) teristics. First, their telomeres are usually massively longer than equivalent telomerase-positive cancer Telomeres consist of 5ʹ-TTAGGG-3ʹ repeats at the cells [9]. Second, the cells contain a large amount of ends of chromosomes. They are shortened by 50–200 extrachromosomal telomeric DNA, some of which is base pairs per cell cycle [1]becausetheDNAreplica- circular and containing regions of single-stranded tion machinery cannot catalyze the complete replica- DNA derived from the C-rich strand (C-circles) [10]. tion of linear molecules (the ‘end replication problem’ Third, the cells display a hyper-recombinogenic phe- [2]). Telomere shortening creates a barrier to tumor- notype in both telomeric and non-telomeric regions igenesis and limits the lifespan of transformed cells [3]. [11]. All of these features point to an altered DNA The majority of carcinomas and almost all hematologic repair process, or at least one that is conducive to malignancies subvert this barrier through activation of elevated telomeric recombination. In particular, the a reverse transcriptase enzyme called telomerase that chromatin of telomeres, normally regulated by histone overcomes telomere shortening by synthesizing new H3.3 and the chromatin remodeler ATRX:DAXX to be telomeric DNA. Telomerase is a target in cancer ther- repressive to transcription and recombination, apy [4,5]; however, not all cancers use telomerase to becomes highly permissive. Indeed, ATRX or DAXX maintain telomeres. Instead, about 10% of carcinomas (mutually exclusive) and H3.3 are obligately mutated and at least 40% of sarcomas use a recombination/ during the development of ALT-positive cancer replication-based mechanism, called Alternative- [11,12]. lengthening of telomeres (ALT) [6]. Sarcomas that Several recent breakthrough studies demonstrate use ALT are more refractory to treatment and carry that ‘break-induced telomere synthesis’ (BITS) (also a higher risk of patient death compared to telomerase- known as telomeric MiDAS, Mitotic DNA synthesis) positive tumors [7]. The ALT mechanism, which is is necessary for the ALT mechanism [13–15]. BITS uniquetotumorcellsandonlyrarelyseeninuntrans- appearstorequireallthesamefactorsasbreak- formed cells [8], therefore represents a potential target induced replication (BIR), a specialized form of for new therapies. CONTACT Andrew J Deans [email protected] Genome Stability Unit, St Vincent’s Institute of Medical Research, 9 Princes St Fitzroy, VIC 3056, Australia. @GenomeStability #Current address: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 222 J. J. O’ROURKE ET AL. homologous recombination (HR). These factors copying material beyond the original breakpoint, lead- include the RAD52, BLM and POLD3 proteins [16]. ing to initiation of lagging strand synthesis of the In proposed models for how BITS works, the process C-strand, also by DNA polymerase δ [13,19]. In cano- begins with the invasion of a resected damaged telo- nical HR, the extension is limited by ‘second end mere end (G rich-strand) into a homologous template, capture’, but with broken telomere ends utilizing the forming a D-loop (Figure 1(a)) [14]. In ALT, there is aberrant templates mentioned above, there is no ‘sec- evidence that this template is: (i) a centromere prox- ond end’ to capture (Figure 1(a)) leading to extension imal sequence of the same chromosome (T-loop), (ii) of the telomere. The continued extension of the circular extrachromosomal telomeric sequences D-loop requires POLD3 and POLD4, accessory sub- (C-circles), (iii) homologous chromosomes, or (iv) units of polymerase δ that are not essential for the other chromosomes (Figure 1(b)). ALT may arise via normalreplicativeroleofthisenzyme.Theexactrole usage of a combination of some or all of these tem- of these two components is unclear, but in vitro they plates [8,17,18]. Importantly, because telomeres are provide increased processivity to polymerase δ [20]. highly repetitive, invasion between or within telo- Because BIR (and by extension, BITS) is restricted by meres is not limited by the requirement in HR for topological constraints, increased processivity is criti- extended homology. After D-loop formation, DNA cal for the extension of kilobases (or even megabases polymerase δ extends the invaded G-strand end, [9]) of telomeric DNA as a single unit. Figure 1. Extension of telomeres during ALT by Break-Induced Telomere Synthesis (BITS) mechanism. (a) Schematic of conservative replication of DNA by break-induced replication. (b) Four potential substrates of the proposed BITS mechanism that can lead to new telomere synthesis by ALT. Created with Biorender.com NUCLEUS 223 The second feature of BITS and BIR is the pro- duction of a non-conservative DNA product; at the conclusion of the copying reaction, both strands contain entirely new DNA. This is different to canonical ‘semi-conservative’ replication, where one strand is newly synthesized, and the other comes from the original template. In this manner, BITS allows entire telomeric sequences to be copied from one chromosome to another, without affect- ing the length or integrity of the copied sequence. Recent work suggests that BIR proceeds via a D-loop migration model, which is supported by observation of non-conservative rather than semi- conservative products of break-induced replication Figure 2. Domain architecture of FANCM protein at a replication fork. The FANCM polypeptide from N- to C-termini is shown in at ALT telomeres [16] and the D-loop-shaped pro- blue. Key domains are highlighted, including N-terminal PIP box ducts observed by two-dimensional gel electro- that binds PCNA, MHF-interaction domain (MID), FANCF interac- phoresis at sites undergoing BIR [21]. tion domain (MM1) and RMI1–RMI2 interaction domain (MM2). Also important to the ALT process are DNA:RNA The DNA binding translocase and ERCC4 domains (bound to FAAP24) are shown in dark blue. Where available, crystal struc- hybrids called R-loops. R-loops form in normal telo- tures are shown. Scale and arrangement are only an approxima- meres at low levels but are highly elevated in ALT cells tion. Created with Biorender.com. [22]. Suppression of these so-called Telomere Extended Repetitive RNAs (TERRAs) by transcription inhibition or overexpression of RNase H (which spe- interaction motifs (Figure 2). In particular, FANCM cifically degrades RNA within a DNA:RNA hybrid) has been shown to bind DNA in a structure-specific leads to reduced proliferation rates in ALT cells, and manner [30]. Two DNA binding domains exist in the shortened telomeres [22,23]. TERRA R-loops are also protein: an N-terminal DEAH domain required for elevated in ATRX-/- telomerase-positive cells [24]. recognition of fork-shaped DNA (described further This indicates that R-loops could be a consequence of below), and a C-terminal ERCC4 pseudo-nuclease the relaxed chromatin environment of ALT telomeres, domain, required for localizing the protein to specific but many R-loop processing factors appear to play DNA damage sites. Despite evolutionary similarity to a role specifically in ALT cells [22]. There is also restriction endonuclease domains, the ERCC4 domain a possibility that TERRAs are used as a substrate to does not cleave DNA, but instead binds structures initiate break-induced replication. In bacteria, or yeast containing dsDNA:ssDNA junctions [31]. EM investi- that lack telomerase, RNA-mediated replication start is gations suggest that the N- and C-terminal DNA bind- acommonlyusedmechanismofreplicationakinto ing domains come together in the overall architecture
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